Handout interaksi obat minggu 4

INTERAKSI OBAT DALAM PROSES DISTRIBUSI

Setelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di mana obat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mengakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat

Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sama terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peningkatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obat bebas atau bentuk aktif akan lebih tinggi

Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin

Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis

Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang

- persen terikat protein tinggi ( lebih dari 90)- terikat pada jaringan- mempunyai volume distribusi yang kecil peningkatan

sedikit thd obat yang dibebaskan akan meningkatkan kadar 2-3 kali lipat terutama berlaku pada obat yang bersifat asam karena kebanyakan obat bersifat basa Vd-nya sangat luas

- mempunyai rasio eksresi hepatic yang rendah- mempunyai rentang terapetik yang sempit peningkatan

kadar obat bebas dapat mencapai tingkat toksik- mempunyai onset aksi yang cepat- digunakan secara intravena

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo yaitu obat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein antara lain adalah fenilbutazon asam salisilat aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) anti inflamasi non steroid Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir

ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

Mekanisme Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

DISTRIBUSI OBAT

Protein plasma

Sebagian besar obat yang bersirkulasi dalam darah terikat secara reversible dengan protein plasma

- Albumin obat yang bersifat asam - α1-acid glycoprotein obat basa- protein plasma lain- protein carrier hormone spesifik thyroxine-binding

globulin CBG (corticosteroid binding globulin) mengikat corticosteroid SSBG (sex steroid binding globulin) mengikat hormone kelamin

oleh karena jumlah protein plasma terbatas maka terjadi kompetisi antara obat bersifat asam maupun antara obat bersifat basa untuk berikatan pada protein yang sama

Fraksi obat total dalam plasma ditentukan oleh

- konsentrasi obat- afinitas binding site- jumlah binding site

keadaan-keadaan tertentu yang menyebabkan perubahan pengikatan protein

- hipoalbuminemia- peningkatan respon acute-phase reaction (ca (cardiac

arrest) arthritis infark miocard Chronrsquos disease) peningkatan kadar α1-acid glycoprotein

kompetisi pengikatan protein plasma peningkatan penurunan konsentrasi obat dalam darah hati-hati pada obat yang safety indexnya kecil

peningkatan kadar obat bebas dalam darah akan menimbulkan peningkatan efek farmakologinya Akan tetapi keadaan ini hanya berlangsung sementara karena peningkatan kadar obat bebas juga akan meningkatkan eliminasinya sehingga akhirnya tercapai keadaan mantap yang baru dimana kadar obat total menurun tetapi kadar obat bebas kembali seperti sebelumnya (mekanisme kompensasi)

pergeseran ikatan protein plasma bermakna secara klinis jika

1 ikatan protein tinggi ge 85 konsentrasi obat bebas rendah

2 Volume distribusi kecil (le 015 Lkg) peningkatan obat bebas tidak habis terdistribusi konsentrasi plasma meningkat bermakna Contoh obat asam karena lebih banyak di luar sel

Contoh fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

3 Batas keamanan sempit peningkatan konsentrasi plasma relative kecil sudah bermakna secara klinis

4 efek toksik yang serius telah terjadi sebelum kompensasi tsb terjadi di atas misalnya terjadi perdarahan pada antikoagulan oral hipoglikemia pada antidiabetik oral

5 eliminasinya mengalami kejenuhan misalnya fenitoin salisilat dan dikumarol sehingga peningkatan kadar obat

bebas tidak disertai dengan peningkatan kecepatan eliminasinya

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier

Interaksi ini lebih nyata pada penderita dengan hipoalbuminemia gagal ginjal atau penyakit hati yang berat akibat berkurangnya jumlah albumin plasma ikatan obat bersifat asam dengan albumin serta menurunnya eliminasi obat

Ikatan jaringan Kebanyakan obat konsentrasi jaringan gt konsentrasi

ECF (cairan ekstra sel) dan darah

Contoh digoksin dan kuinidin berkompetisi untuk berikatan dalam jaringan peningkatan kadar plasma digoksin

Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Ikatan di jaringan terjadi dengan konstituen sel protein fosfolipid protein inti biasanya reversible

Obat di jaringan reservoir memperpanjang kerja obat di jaringan dapat terjadi toksisitas local Misal

- kuinakrin hati- DDT jaringan lemak - Pb tulang - klorpromazin otak - digoksin otot jantung dan otot skelet

Redistribusi Obat dihentikan efek berakhir oleh karena terjadi

redistribusi obat dari tempat kerja jaringan tertentu Saat obat-obat yang sangat larut lemak diberikan dengan

injeksi IVinhalasi konsentrasi max dalam otak dalam beberapa detik obat berdifusi ke jaringan lain konsentrasi plasma turun efek hilang onset cepat terminasi cepat

CNS (Central Nervous System) dan CSF BBB (Blood Brain Barrier) continous tight junction sel

endothelial kapiler otak dan sel glial perikapiler (sel endothelial kapiler otak dan sel glial perikapiler dihubungkan dengan sambungan yang sangat rapat) penetrasi obat ke otak tergantung transport transeluler

Blood-CSF barrier plexus choroid = epitel tight junctions Uptake oleh otak sebanding dengan kelarutan dalam

lemak dari obat bebas dan dalam bentuk tidak terionisasi (nonionized)

Obat juga dapat menembus CNS dengan transporter spesifik

Transfer Transplasenta Obat dapat menyebabkan kelainan janin Ditentukan oleh

o Kelarutan lemako Ikatan protein plasmao Derajat ionisasi asam dan basa lemah

Plasma janin sedikit lebih asam daripada ibu (pH 70 ndash 72) terjadi ion trapping obat-obat basa (terjadi reaksi asam basa thd obat-obat basa)

P-gp melindungi fetus dari obat yang merugikan

MEKANISME FARMAKOKINETIK

Distribusi1 Kompetisi untuk pengikatan oleh protein plasma

meningkatkan konsentrasi obat bebas peningkatan sementara oleh karena efek kompensatorik

2 Menggeser dari tempat ikatan di jaringan biasanya tidak menyebabkan ES

3 Mengubah local barrier jaringan mis P-glycoprotein inhibition di BBB

Obat absorpsi aliran darah cairan interstitial dan intraseluler

Laju distribusi obat tergantung CO (cardiac output) aliran darah setempat permeabilitas kapiler dan volume jaringan

Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Distribusi fase 2 otot visera kulit dan jaringan lemak (butuh beberapa menit ndash jam konsentrasi obat di darah = jaringan

Interaksi pada fase distribusi

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo antara lain adalah fenilbutazon aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

1 Distribusi

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

w

KETR

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis

Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang

- persen terikat protein tinggi ( lebih dari 90)- terikat pada jaringan- mempunyai volume distribusi yang kecil peningkatan

sedikit thd obat yang dibebaskan akan meningkatkan kadar 2-3 kali lipat terutama berlaku pada obat yang bersifat asam karena kebanyakan obat bersifat basa Vd-nya sangat luas

- mempunyai rasio eksresi hepatic yang rendah- mempunyai rentang terapetik yang sempit peningkatan

kadar obat bebas dapat mencapai tingkat toksik- mempunyai onset aksi yang cepat- digunakan secara intravena

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo yaitu obat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein antara lain adalah fenilbutazon asam salisilat aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) anti inflamasi non steroid Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir

ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

Mekanisme Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

DISTRIBUSI OBAT

Protein plasma

Sebagian besar obat yang bersirkulasi dalam darah terikat secara reversible dengan protein plasma

- Albumin obat yang bersifat asam - α1-acid glycoprotein obat basa- protein plasma lain- protein carrier hormone spesifik thyroxine-binding

globulin CBG (corticosteroid binding globulin) mengikat corticosteroid SSBG (sex steroid binding globulin) mengikat hormone kelamin

oleh karena jumlah protein plasma terbatas maka terjadi kompetisi antara obat bersifat asam maupun antara obat bersifat basa untuk berikatan pada protein yang sama

Fraksi obat total dalam plasma ditentukan oleh

- konsentrasi obat- afinitas binding site- jumlah binding site

keadaan-keadaan tertentu yang menyebabkan perubahan pengikatan protein

- hipoalbuminemia- peningkatan respon acute-phase reaction (ca (cardiac

arrest) arthritis infark miocard Chronrsquos disease) peningkatan kadar α1-acid glycoprotein

kompetisi pengikatan protein plasma peningkatan penurunan konsentrasi obat dalam darah hati-hati pada obat yang safety indexnya kecil

peningkatan kadar obat bebas dalam darah akan menimbulkan peningkatan efek farmakologinya Akan tetapi keadaan ini hanya berlangsung sementara karena peningkatan kadar obat bebas juga akan meningkatkan eliminasinya sehingga akhirnya tercapai keadaan mantap yang baru dimana kadar obat total menurun tetapi kadar obat bebas kembali seperti sebelumnya (mekanisme kompensasi)

pergeseran ikatan protein plasma bermakna secara klinis jika

1 ikatan protein tinggi ge 85 konsentrasi obat bebas rendah

2 Volume distribusi kecil (le 015 Lkg) peningkatan obat bebas tidak habis terdistribusi konsentrasi plasma meningkat bermakna Contoh obat asam karena lebih banyak di luar sel

Contoh fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

3 Batas keamanan sempit peningkatan konsentrasi plasma relative kecil sudah bermakna secara klinis

4 efek toksik yang serius telah terjadi sebelum kompensasi tsb terjadi di atas misalnya terjadi perdarahan pada antikoagulan oral hipoglikemia pada antidiabetik oral

5 eliminasinya mengalami kejenuhan misalnya fenitoin salisilat dan dikumarol sehingga peningkatan kadar obat

bebas tidak disertai dengan peningkatan kecepatan eliminasinya

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier

Interaksi ini lebih nyata pada penderita dengan hipoalbuminemia gagal ginjal atau penyakit hati yang berat akibat berkurangnya jumlah albumin plasma ikatan obat bersifat asam dengan albumin serta menurunnya eliminasi obat

Ikatan jaringan Kebanyakan obat konsentrasi jaringan gt konsentrasi

ECF (cairan ekstra sel) dan darah

Contoh digoksin dan kuinidin berkompetisi untuk berikatan dalam jaringan peningkatan kadar plasma digoksin

Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Ikatan di jaringan terjadi dengan konstituen sel protein fosfolipid protein inti biasanya reversible

Obat di jaringan reservoir memperpanjang kerja obat di jaringan dapat terjadi toksisitas local Misal

- kuinakrin hati- DDT jaringan lemak - Pb tulang - klorpromazin otak - digoksin otot jantung dan otot skelet

Redistribusi Obat dihentikan efek berakhir oleh karena terjadi

redistribusi obat dari tempat kerja jaringan tertentu Saat obat-obat yang sangat larut lemak diberikan dengan

injeksi IVinhalasi konsentrasi max dalam otak dalam beberapa detik obat berdifusi ke jaringan lain konsentrasi plasma turun efek hilang onset cepat terminasi cepat

CNS (Central Nervous System) dan CSF BBB (Blood Brain Barrier) continous tight junction sel

endothelial kapiler otak dan sel glial perikapiler (sel endothelial kapiler otak dan sel glial perikapiler dihubungkan dengan sambungan yang sangat rapat) penetrasi obat ke otak tergantung transport transeluler

Blood-CSF barrier plexus choroid = epitel tight junctions Uptake oleh otak sebanding dengan kelarutan dalam

lemak dari obat bebas dan dalam bentuk tidak terionisasi (nonionized)

Obat juga dapat menembus CNS dengan transporter spesifik

Transfer Transplasenta Obat dapat menyebabkan kelainan janin Ditentukan oleh

o Kelarutan lemako Ikatan protein plasmao Derajat ionisasi asam dan basa lemah

Plasma janin sedikit lebih asam daripada ibu (pH 70 ndash 72) terjadi ion trapping obat-obat basa (terjadi reaksi asam basa thd obat-obat basa)

P-gp melindungi fetus dari obat yang merugikan

MEKANISME FARMAKOKINETIK

Distribusi1 Kompetisi untuk pengikatan oleh protein plasma

meningkatkan konsentrasi obat bebas peningkatan sementara oleh karena efek kompensatorik

2 Menggeser dari tempat ikatan di jaringan biasanya tidak menyebabkan ES

3 Mengubah local barrier jaringan mis P-glycoprotein inhibition di BBB

Obat absorpsi aliran darah cairan interstitial dan intraseluler

Laju distribusi obat tergantung CO (cardiac output) aliran darah setempat permeabilitas kapiler dan volume jaringan

Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Distribusi fase 2 otot visera kulit dan jaringan lemak (butuh beberapa menit ndash jam konsentrasi obat di darah = jaringan

Interaksi pada fase distribusi

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo antara lain adalah fenilbutazon aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

1 Distribusi

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

w

KETR

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

Mekanisme Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

DISTRIBUSI OBAT

Protein plasma

Sebagian besar obat yang bersirkulasi dalam darah terikat secara reversible dengan protein plasma

- Albumin obat yang bersifat asam - α1-acid glycoprotein obat basa- protein plasma lain- protein carrier hormone spesifik thyroxine-binding

globulin CBG (corticosteroid binding globulin) mengikat corticosteroid SSBG (sex steroid binding globulin) mengikat hormone kelamin

oleh karena jumlah protein plasma terbatas maka terjadi kompetisi antara obat bersifat asam maupun antara obat bersifat basa untuk berikatan pada protein yang sama

Fraksi obat total dalam plasma ditentukan oleh

- konsentrasi obat- afinitas binding site- jumlah binding site

keadaan-keadaan tertentu yang menyebabkan perubahan pengikatan protein

- hipoalbuminemia- peningkatan respon acute-phase reaction (ca (cardiac

arrest) arthritis infark miocard Chronrsquos disease) peningkatan kadar α1-acid glycoprotein

kompetisi pengikatan protein plasma peningkatan penurunan konsentrasi obat dalam darah hati-hati pada obat yang safety indexnya kecil

peningkatan kadar obat bebas dalam darah akan menimbulkan peningkatan efek farmakologinya Akan tetapi keadaan ini hanya berlangsung sementara karena peningkatan kadar obat bebas juga akan meningkatkan eliminasinya sehingga akhirnya tercapai keadaan mantap yang baru dimana kadar obat total menurun tetapi kadar obat bebas kembali seperti sebelumnya (mekanisme kompensasi)

pergeseran ikatan protein plasma bermakna secara klinis jika

1 ikatan protein tinggi ge 85 konsentrasi obat bebas rendah

2 Volume distribusi kecil (le 015 Lkg) peningkatan obat bebas tidak habis terdistribusi konsentrasi plasma meningkat bermakna Contoh obat asam karena lebih banyak di luar sel

Contoh fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

3 Batas keamanan sempit peningkatan konsentrasi plasma relative kecil sudah bermakna secara klinis

4 efek toksik yang serius telah terjadi sebelum kompensasi tsb terjadi di atas misalnya terjadi perdarahan pada antikoagulan oral hipoglikemia pada antidiabetik oral

5 eliminasinya mengalami kejenuhan misalnya fenitoin salisilat dan dikumarol sehingga peningkatan kadar obat

bebas tidak disertai dengan peningkatan kecepatan eliminasinya

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier

Interaksi ini lebih nyata pada penderita dengan hipoalbuminemia gagal ginjal atau penyakit hati yang berat akibat berkurangnya jumlah albumin plasma ikatan obat bersifat asam dengan albumin serta menurunnya eliminasi obat

Ikatan jaringan Kebanyakan obat konsentrasi jaringan gt konsentrasi

ECF (cairan ekstra sel) dan darah

Contoh digoksin dan kuinidin berkompetisi untuk berikatan dalam jaringan peningkatan kadar plasma digoksin

Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Ikatan di jaringan terjadi dengan konstituen sel protein fosfolipid protein inti biasanya reversible

Obat di jaringan reservoir memperpanjang kerja obat di jaringan dapat terjadi toksisitas local Misal

- kuinakrin hati- DDT jaringan lemak - Pb tulang - klorpromazin otak - digoksin otot jantung dan otot skelet

Redistribusi Obat dihentikan efek berakhir oleh karena terjadi

redistribusi obat dari tempat kerja jaringan tertentu Saat obat-obat yang sangat larut lemak diberikan dengan

injeksi IVinhalasi konsentrasi max dalam otak dalam beberapa detik obat berdifusi ke jaringan lain konsentrasi plasma turun efek hilang onset cepat terminasi cepat

CNS (Central Nervous System) dan CSF BBB (Blood Brain Barrier) continous tight junction sel

endothelial kapiler otak dan sel glial perikapiler (sel endothelial kapiler otak dan sel glial perikapiler dihubungkan dengan sambungan yang sangat rapat) penetrasi obat ke otak tergantung transport transeluler

Blood-CSF barrier plexus choroid = epitel tight junctions Uptake oleh otak sebanding dengan kelarutan dalam

lemak dari obat bebas dan dalam bentuk tidak terionisasi (nonionized)

Obat juga dapat menembus CNS dengan transporter spesifik

Transfer Transplasenta Obat dapat menyebabkan kelainan janin Ditentukan oleh

o Kelarutan lemako Ikatan protein plasmao Derajat ionisasi asam dan basa lemah

Plasma janin sedikit lebih asam daripada ibu (pH 70 ndash 72) terjadi ion trapping obat-obat basa (terjadi reaksi asam basa thd obat-obat basa)

P-gp melindungi fetus dari obat yang merugikan

MEKANISME FARMAKOKINETIK

Distribusi1 Kompetisi untuk pengikatan oleh protein plasma

meningkatkan konsentrasi obat bebas peningkatan sementara oleh karena efek kompensatorik

2 Menggeser dari tempat ikatan di jaringan biasanya tidak menyebabkan ES

3 Mengubah local barrier jaringan mis P-glycoprotein inhibition di BBB

Obat absorpsi aliran darah cairan interstitial dan intraseluler

Laju distribusi obat tergantung CO (cardiac output) aliran darah setempat permeabilitas kapiler dan volume jaringan

Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Distribusi fase 2 otot visera kulit dan jaringan lemak (butuh beberapa menit ndash jam konsentrasi obat di darah = jaringan

Interaksi pada fase distribusi

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo antara lain adalah fenilbutazon aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

1 Distribusi

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

w

KETR

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

- hipoalbuminemia- peningkatan respon acute-phase reaction (ca (cardiac

arrest) arthritis infark miocard Chronrsquos disease) peningkatan kadar α1-acid glycoprotein

kompetisi pengikatan protein plasma peningkatan penurunan konsentrasi obat dalam darah hati-hati pada obat yang safety indexnya kecil

peningkatan kadar obat bebas dalam darah akan menimbulkan peningkatan efek farmakologinya Akan tetapi keadaan ini hanya berlangsung sementara karena peningkatan kadar obat bebas juga akan meningkatkan eliminasinya sehingga akhirnya tercapai keadaan mantap yang baru dimana kadar obat total menurun tetapi kadar obat bebas kembali seperti sebelumnya (mekanisme kompensasi)

pergeseran ikatan protein plasma bermakna secara klinis jika

1 ikatan protein tinggi ge 85 konsentrasi obat bebas rendah

2 Volume distribusi kecil (le 015 Lkg) peningkatan obat bebas tidak habis terdistribusi konsentrasi plasma meningkat bermakna Contoh obat asam karena lebih banyak di luar sel

Contoh fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

3 Batas keamanan sempit peningkatan konsentrasi plasma relative kecil sudah bermakna secara klinis

4 efek toksik yang serius telah terjadi sebelum kompensasi tsb terjadi di atas misalnya terjadi perdarahan pada antikoagulan oral hipoglikemia pada antidiabetik oral

5 eliminasinya mengalami kejenuhan misalnya fenitoin salisilat dan dikumarol sehingga peningkatan kadar obat

bebas tidak disertai dengan peningkatan kecepatan eliminasinya

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier

Interaksi ini lebih nyata pada penderita dengan hipoalbuminemia gagal ginjal atau penyakit hati yang berat akibat berkurangnya jumlah albumin plasma ikatan obat bersifat asam dengan albumin serta menurunnya eliminasi obat

Ikatan jaringan Kebanyakan obat konsentrasi jaringan gt konsentrasi

ECF (cairan ekstra sel) dan darah

Contoh digoksin dan kuinidin berkompetisi untuk berikatan dalam jaringan peningkatan kadar plasma digoksin

Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Ikatan di jaringan terjadi dengan konstituen sel protein fosfolipid protein inti biasanya reversible

Obat di jaringan reservoir memperpanjang kerja obat di jaringan dapat terjadi toksisitas local Misal

- kuinakrin hati- DDT jaringan lemak - Pb tulang - klorpromazin otak - digoksin otot jantung dan otot skelet

Redistribusi Obat dihentikan efek berakhir oleh karena terjadi

redistribusi obat dari tempat kerja jaringan tertentu Saat obat-obat yang sangat larut lemak diberikan dengan

injeksi IVinhalasi konsentrasi max dalam otak dalam beberapa detik obat berdifusi ke jaringan lain konsentrasi plasma turun efek hilang onset cepat terminasi cepat

CNS (Central Nervous System) dan CSF BBB (Blood Brain Barrier) continous tight junction sel

endothelial kapiler otak dan sel glial perikapiler (sel endothelial kapiler otak dan sel glial perikapiler dihubungkan dengan sambungan yang sangat rapat) penetrasi obat ke otak tergantung transport transeluler

Blood-CSF barrier plexus choroid = epitel tight junctions Uptake oleh otak sebanding dengan kelarutan dalam

lemak dari obat bebas dan dalam bentuk tidak terionisasi (nonionized)

Obat juga dapat menembus CNS dengan transporter spesifik

Transfer Transplasenta Obat dapat menyebabkan kelainan janin Ditentukan oleh

o Kelarutan lemako Ikatan protein plasmao Derajat ionisasi asam dan basa lemah

Plasma janin sedikit lebih asam daripada ibu (pH 70 ndash 72) terjadi ion trapping obat-obat basa (terjadi reaksi asam basa thd obat-obat basa)

P-gp melindungi fetus dari obat yang merugikan

MEKANISME FARMAKOKINETIK

Distribusi1 Kompetisi untuk pengikatan oleh protein plasma

meningkatkan konsentrasi obat bebas peningkatan sementara oleh karena efek kompensatorik

2 Menggeser dari tempat ikatan di jaringan biasanya tidak menyebabkan ES

3 Mengubah local barrier jaringan mis P-glycoprotein inhibition di BBB

Obat absorpsi aliran darah cairan interstitial dan intraseluler

Laju distribusi obat tergantung CO (cardiac output) aliran darah setempat permeabilitas kapiler dan volume jaringan

Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Distribusi fase 2 otot visera kulit dan jaringan lemak (butuh beberapa menit ndash jam konsentrasi obat di darah = jaringan

Interaksi pada fase distribusi

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo antara lain adalah fenilbutazon aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

1 Distribusi

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

w

KETR

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

bebas tidak disertai dengan peningkatan kecepatan eliminasinya

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier

Interaksi ini lebih nyata pada penderita dengan hipoalbuminemia gagal ginjal atau penyakit hati yang berat akibat berkurangnya jumlah albumin plasma ikatan obat bersifat asam dengan albumin serta menurunnya eliminasi obat

Ikatan jaringan Kebanyakan obat konsentrasi jaringan gt konsentrasi

ECF (cairan ekstra sel) dan darah

Contoh digoksin dan kuinidin berkompetisi untuk berikatan dalam jaringan peningkatan kadar plasma digoksin

Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Ikatan di jaringan terjadi dengan konstituen sel protein fosfolipid protein inti biasanya reversible

Obat di jaringan reservoir memperpanjang kerja obat di jaringan dapat terjadi toksisitas local Misal

- kuinakrin hati- DDT jaringan lemak - Pb tulang - klorpromazin otak - digoksin otot jantung dan otot skelet

Redistribusi Obat dihentikan efek berakhir oleh karena terjadi

redistribusi obat dari tempat kerja jaringan tertentu Saat obat-obat yang sangat larut lemak diberikan dengan

injeksi IVinhalasi konsentrasi max dalam otak dalam beberapa detik obat berdifusi ke jaringan lain konsentrasi plasma turun efek hilang onset cepat terminasi cepat

CNS (Central Nervous System) dan CSF BBB (Blood Brain Barrier) continous tight junction sel

endothelial kapiler otak dan sel glial perikapiler (sel endothelial kapiler otak dan sel glial perikapiler dihubungkan dengan sambungan yang sangat rapat) penetrasi obat ke otak tergantung transport transeluler

Blood-CSF barrier plexus choroid = epitel tight junctions Uptake oleh otak sebanding dengan kelarutan dalam

lemak dari obat bebas dan dalam bentuk tidak terionisasi (nonionized)

Obat juga dapat menembus CNS dengan transporter spesifik

Transfer Transplasenta Obat dapat menyebabkan kelainan janin Ditentukan oleh

o Kelarutan lemako Ikatan protein plasmao Derajat ionisasi asam dan basa lemah

Plasma janin sedikit lebih asam daripada ibu (pH 70 ndash 72) terjadi ion trapping obat-obat basa (terjadi reaksi asam basa thd obat-obat basa)

P-gp melindungi fetus dari obat yang merugikan

MEKANISME FARMAKOKINETIK

Distribusi1 Kompetisi untuk pengikatan oleh protein plasma

meningkatkan konsentrasi obat bebas peningkatan sementara oleh karena efek kompensatorik

2 Menggeser dari tempat ikatan di jaringan biasanya tidak menyebabkan ES

3 Mengubah local barrier jaringan mis P-glycoprotein inhibition di BBB

Obat absorpsi aliran darah cairan interstitial dan intraseluler

Laju distribusi obat tergantung CO (cardiac output) aliran darah setempat permeabilitas kapiler dan volume jaringan

Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Distribusi fase 2 otot visera kulit dan jaringan lemak (butuh beberapa menit ndash jam konsentrasi obat di darah = jaringan

Interaksi pada fase distribusi

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo antara lain adalah fenilbutazon aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

1 Distribusi

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

w

KETR

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Obat di jaringan reservoir memperpanjang kerja obat di jaringan dapat terjadi toksisitas local Misal

- kuinakrin hati- DDT jaringan lemak - Pb tulang - klorpromazin otak - digoksin otot jantung dan otot skelet

Redistribusi Obat dihentikan efek berakhir oleh karena terjadi

redistribusi obat dari tempat kerja jaringan tertentu Saat obat-obat yang sangat larut lemak diberikan dengan

injeksi IVinhalasi konsentrasi max dalam otak dalam beberapa detik obat berdifusi ke jaringan lain konsentrasi plasma turun efek hilang onset cepat terminasi cepat

CNS (Central Nervous System) dan CSF BBB (Blood Brain Barrier) continous tight junction sel

endothelial kapiler otak dan sel glial perikapiler (sel endothelial kapiler otak dan sel glial perikapiler dihubungkan dengan sambungan yang sangat rapat) penetrasi obat ke otak tergantung transport transeluler

Blood-CSF barrier plexus choroid = epitel tight junctions Uptake oleh otak sebanding dengan kelarutan dalam

lemak dari obat bebas dan dalam bentuk tidak terionisasi (nonionized)

Obat juga dapat menembus CNS dengan transporter spesifik

Transfer Transplasenta Obat dapat menyebabkan kelainan janin Ditentukan oleh

o Kelarutan lemako Ikatan protein plasmao Derajat ionisasi asam dan basa lemah

Plasma janin sedikit lebih asam daripada ibu (pH 70 ndash 72) terjadi ion trapping obat-obat basa (terjadi reaksi asam basa thd obat-obat basa)

P-gp melindungi fetus dari obat yang merugikan

MEKANISME FARMAKOKINETIK

Distribusi1 Kompetisi untuk pengikatan oleh protein plasma

meningkatkan konsentrasi obat bebas peningkatan sementara oleh karena efek kompensatorik

2 Menggeser dari tempat ikatan di jaringan biasanya tidak menyebabkan ES

3 Mengubah local barrier jaringan mis P-glycoprotein inhibition di BBB

Obat absorpsi aliran darah cairan interstitial dan intraseluler

Laju distribusi obat tergantung CO (cardiac output) aliran darah setempat permeabilitas kapiler dan volume jaringan

Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Distribusi fase 2 otot visera kulit dan jaringan lemak (butuh beberapa menit ndash jam konsentrasi obat di darah = jaringan

Interaksi pada fase distribusi

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo antara lain adalah fenilbutazon aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

1 Distribusi

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

w

KETR

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

o Kelarutan lemako Ikatan protein plasmao Derajat ionisasi asam dan basa lemah

Plasma janin sedikit lebih asam daripada ibu (pH 70 ndash 72) terjadi ion trapping obat-obat basa (terjadi reaksi asam basa thd obat-obat basa)

P-gp melindungi fetus dari obat yang merugikan

MEKANISME FARMAKOKINETIK

Distribusi1 Kompetisi untuk pengikatan oleh protein plasma

meningkatkan konsentrasi obat bebas peningkatan sementara oleh karena efek kompensatorik

2 Menggeser dari tempat ikatan di jaringan biasanya tidak menyebabkan ES

3 Mengubah local barrier jaringan mis P-glycoprotein inhibition di BBB

Obat absorpsi aliran darah cairan interstitial dan intraseluler

Laju distribusi obat tergantung CO (cardiac output) aliran darah setempat permeabilitas kapiler dan volume jaringan

Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Distribusi fase 2 otot visera kulit dan jaringan lemak (butuh beberapa menit ndash jam konsentrasi obat di darah = jaringan

Interaksi pada fase distribusi

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo antara lain adalah fenilbutazon aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

1 Distribusi

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

w

KETR

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Interaksi pada fase distribusi

Interaksi terutama terjadi pada obat-obat yang berkompetisi untuk berikatan dengan protein plasma Terdapat beberapa macam obat yang disebut ldquodisplacing agentrdquo antara lain adalah fenilbutazon aspirin sulfonamid dan trikloroasetat (matabolit dari kloralhidrat) Obat-obat ini pada dosis yang cukup tinggi dapat mengusir obat lain dari ikatannya pada protein plasma Obat-obat yang bisa terusir antara lain warfarin (antikoagulan oral) tolbutamid (antidiabetik oral) dan metotreksat (anti kanker)

Pemberian sulfonamid pada neonatus dapat menyebabkan gejala yang disebut ldquokernikterusrdquo karena sulfa dapat mengusir ldquobilirubin tak terkonyugasirdquo dari protein plasma Selanjutnya bilirubin bebas ini dapat merusak otak bayi

1 Distribusi

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

w

KETR

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

SENYAWA LIPOFILIK

SENYAWA HIDROFILIK

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak aktif sepertialbumin (pada darah) otot tulang lemak atau liverPerlu diingat bahwa1048698 Efek suatu obat tergantung kepada konsentrasi obat di tempataksinya (reseptor)1048698 Hanya obat dalam bentuk bebas (tidak terikat) yang dapat denganbekerja di tempat aksinya menghasilkan efek1048698 Obat terikat dan tidak terikat berada dalam kesetimbangan dalamdarah digambarkan dgn persamaan sbb

D + A harr DA

Efek ikatan depot terhadap efek terapi

Interaksi yang terjadipada proses distribusiMekanisme interaksi yang melibatkan proses distribusi terjadi karena pergeseran ikatan protein plasma Interaksi obat yang melibatkan proses distribusi akan bermakna klinik jika (1) obat indeks memiliki ikatan protein sebesar gt 85 volume distribusi (Vd) obat lt 015 Ikg dan memiliki batas keamanan sempit (2) obat presipitan berikatan dengan albumin pada tempat ikatan (finding site) yang sama dengan obat indeks serta kadarnya cukup tinggi untuk menempati dan menjenuhkan binding-site nya [9] Contohnya fenilbutazon dapat menggeser warfarin (ikatan protein 99 Vd = 014 Ikg) dan tolbutamid (ikatan protein 96 Vd = 012 Ikg) sehingga kadar plasma warfarin dan tolbutamid bebas meningkat Selain itu fenilbutazon juga menghambat metabolisme warfarin dan tolbutamid

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Distribusi Obat

Pergeseran obat dari binding site di plasma atau jaringan dapat meningkatkan kadar obat bebas tak terikat tetapi hal ini diikuti dengan peningkatan eliminasi sehingga terjadi steady state baru dimana kadar obat total di plasma menurun tetapi kadar obat bebas sama dengan sebelum digeser oleh obat lain Ada beberapa keadaan klinis yang penting

Dapat terjadi toksisitas apabila kadar obat bebas meningkat sebelum steady state yang baru tercapai

Apabila merubah dosis untuk memenuhi target kadar plasma total harus diingat bahwa kadar terapetik target akan dipengaruhi oleh obat yang menggeser

Bila obat kedua yang menggeser menurunkan eliminasi obat pertama maka kadar obat bebas meningkat bukan hanya akut tetapi juga kronis pada steady state yang baru dapat menyebabkan toksisitas berat

Distribusi obat dipengaruhi oleh obat lain yang berkompetisi terhadap ikatan dengan protein plasma Misalnya antibiotik sulfonamide dapat menggeser methotrexate phenytoin sulfonylurea dan warfarin dari ikatannya dengan albumin Sulfonamide chloral hydrate trichloracetic acid (metabolit chloral hydrate) mengikat erat plasma albumin

Penggeseran bilirubin dari albumin oleh obat pada neonatus prematur yang jaundice dapat berakibat serius karena pada bayi prematur metabolisme bilirubin masih belum sempurna dan bilirubin bebas dapat menembus sawar darah otak yang prematur dan menyebabkan kern icterus (bilirubin menodai basal ganglia) Hal ini menyebabkan gangguan pergerakan yang disebut dengan choreoathetosis gejalanya adalah involuntary writhing dan twisting movements pada anak-anak

Dosis Phenytoin disesuaikan dengan kadar dalam plasma tetapi pengukuran ini tidak membedakan antara phenytoin yang terikat ataupun yang bebas tapi merupakan kadar total obat Pemberian obat penggeser pada pasien epilepsi yang menggunakan phenytoin akan menurunkan kadar phenytoin plasma total sehingga menyebabkan peningkatan eliminasi obat bebas tetapi hal ini tidak menyebabkan hilangnya efikasi karena kadar phenytoin bebas (aktif) pada keadaan steady state yang baru tidak terpengaruh Dalam hal ini kadar plasma dalam index terapetik akan menurun sehingga dosis ditingkatkan menyebabkan toksisitas

Obat yang mempengaruhi ikatan protein dapat menurunkan eliminasi obat yang tergeser menyebabkan interaksi obat Phenylbutazone menggeser warfarin dari ikatannya dengan albumin dan secara selektif meng-inhibisi metabolisme senyawa (S)-isomer yang aktif secara farmakologis memperpanjang prothrombin time dan menyebabkan peningkatan perdarahan Salicylate menggeser methotrexate dari ikatannya dengan albumin dan menurunkan sekresinya ke dalam nephron oleh kompetisi dengan anion secretory carrier Quinidine dan beberapa obat antidysrhythmic lainnya seperti verapamil dan amiodarone menggeser digoxin dari tissue-binding site serta menurunkan ekskresi renal sehingga menyebabkan dysrhythmia berat karena toksisitas digoxin

Perubahan distribusi obat pada suatu senyawa dapat terjadi bila ada senyawa lain yang mempengaruhi ukuran kompartemen fisiknya Misalnya diuretik yang menurunkan total cairan tubuh menyebabkan peningkatan kadar plasma aminoglycoside dan lithium sehingga meningkatkan toksisitasnya

kemungkinan terjadinya interaksi sangat kecil bagi orang ndash orang normal Interaksi dalam fase distribusi sesungguhnya berkaitan dengan pendistribusian zat aktif ke seluruh tubuh Yang paling berpengaruh pada pendistribusian ini adalah protein plasma(albumin)

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Oleh karena itu interaksi ini akan sering terjadi pada pasien yang hipoalbuminemia gagal ginjal atau penyakit hati yang berat ikatan obat yang asam dengan albumin serta menurunnya eliminasi obat Biasanya dokter sebelum menginjeksikan obat pada orang ndash orang hipoalbumin beliau menginjeksikan albumin terlebih dahulu agar obat bisa didistribusikan dengan baik Hal ini sangat diperhatikan terlebih ndash lebih apabila obat memiliki sifat

punya ikatan kuat dengan protein plasma (85 amp Vd kecil)

indeks terapi sempit Berkaitan dengan toksisitas obat dalam darah jika tidak terikat dengan protein albumin

Ikatan protein yang dipindahkanContoh ikatan protein tinggi Phenytoin (90) Tolbutamide (96) dan warfarin (99) akan memindahkan agent Aspirin sulfonamid penilbutason

1DistribusiSetelah obat diabsorpsi ke dalam sistem sirkulasi obat di bawa ke tempat kerja di manaobat akan bereaksi dengan berbagai jaringan tubuh dan atau reseptor Selama berada di aliran darah obat dapat terikat pada berbagai komponen darah terutama protein albumin Obat-obat larut lemak mempunyai afinitas yang tinggi pada jaringan adiposa sehingga obat-obat dapat tersimpan di jaringan adiposa ini Rendahnya aliran darah ke jaringan lemak mersquorsquongakibatkan jaringan ini menjadi depot untuk obat-obat larut lemak Hal ini memperpanjang efek obat Obat-obat yang sangat larut lemak misalnya golongan fenotiazin benzodiazepin dan barbiturat Sejumlah obat yang bersifat asam mempunyai afinitas terhadap protein darah terutama albumin Obat-obat yang bersifat basa mempunyai afinitas untuk berikatan dengan asam-α-glikoprotein Ikatan protein plasma (PPB plasma protein binding) dinyatakan sebagai persen yang menunjukkan persen obat yang terikat Obat yang terikat albumin secara farmakologi tidak aktif sedangkan obat yang tidak terikat biasa disebut fraksi bebas aktif secara farmakologi Bila dua atau lebih obat yang sangat terikat protein digunakan bersama-sasam terjadi kompetisi pengikatan pada tempat yang sama yang mengakibatkan terjadi penggeseran salah satu obat dari ikatan dengan protein dan akhirnya terjadi peninggatan kadar obat bebas dalam darah Bila satu obat tergeser dari ikatannya dengan protein oleh obat lain akan terjadi peningkatan kadar obat bebas yang terdistribusi melewati berbagai jaringan Pada pasien dengan hipoalbuminemia kadar obatbebas atau bentuk aktif akan lebih tinggi Asam valproat dilaporkan menggeser fenitoin dari ikatannya dengan protein dan juga menghambat metabolisme fenitoin Jika pasien mengkonsumsi kedua obat ini kadar fenitoin tak terikat akan meningkat secara signifikan menyebabkan efek samping yang lebih besar Sebaliknya fenitoin dapat menurunkan kadar plasma asam valproat Terapi kombinasi kedua obat ini harus dimonitor dengan ketat serta dilakukan penyesuaian dosis Obat-obat yang cenderung berinteraksi pada proses distribusi adalah obat-obat yang a persen terikat protein tinggi ( lebih dari 90)b terikat pada jaringanc mempunyai volume distribusi yang kecild mempunyai rasio eksresi hepatic yang rendahe mempunyai rentang terapetik yang sempitf mempunyai onset aksi yang cepatg digunakan secara intravenaObat-obat yang mempunyai kemampuan tinggi untuk menggeser obat lain dari ikatan dengan protein adalah asam salisilat fenilbutazon sulfonamid dan anti-inflamasi nonsteroid

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

A TRANSPORTASI OBAT DALAM ALIRAN DARAH

Mekanisme perpindahantransport obat yang dapat menyebabkan terjadinya interaksi pada tahap distribusi adalah transportasi obat secara aktif dimana terjadi perpindahan obatsenyawa dari kompartemen yang berkonsentrasi rendah ke konsentrasi tinggi membutuhkan energi dan protein pembawacarrier ini merupakan mekanisme transport obat-obat tertentu

KETR SENYAWA LIPOFILIKSENYAWA HIDROFILIK

B PENGGESERAN OBAT DARI IKATAN PROTEIN

15 Drug transporter proteins

Drugs and endogenous substances are known to cross biological membranes not just by passive diffusion but by carrier-mediated processes often known as transporters Significant advances in the identification of various transporters have been made although the contribution of many of these to drug interactions in particular is still unclear12 The most well known is P-glycoprotein which is a product of the MDR1 gene (ABCB1 gene) and a member of the ATP-binding cassette (ABC) family of efflux transporters1 Its involvement in drug interactions is discussed in (a) below Another ABC transporter is sister P-glycoprotein otherwise called the bile salt export pump (BSEP or ABCB11)1 It has been suggested that inhibitionof this pump may increase the risk of cholestasis see Drug transporters under lsquoDrug excretion interactionsrsquo (p7)

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

Other transporters that are involved in some drug interactions are the organic anion transporters (OATs) organic anion-transporting polypeptides (OATPs) and organic cation transporters (OCTs) which are members of the solute carrier superfamily (SLC) of transporters1 The best known example of an OAT inhibitor is probenecid which affects the renal excretion of a number of drugs see Changes in active kidney tubule excretion under lsquoDrug excretion interactionsrsquo (p7)(a) P-glycoprotein interactionsMore and more evidence is accumulating to show that some drug interactionsoccur because they interfere with the activity of P-glycoprotein This is an efflux pump found in the membranes of certain cells which can push metabolites and drugs out of the cells and have an impact on the extent of drug absorption (via the intestine) distribution (to the brain testis or placenta)and elimination (in the urine and bile) So for example the P-glycoprotein in the cells of the gut lining can eject some already-absorbed drug molecules back into the intestine resulting in a reduction in the total amount of drug absorbed In this way P-glycoprotein acts as a barrier to absorption The activity of P-glycoprotein in the endothelial cells of the blood-brain barrier can also eject certain drugs from the brain limiting CNS penetration and effects The pumping actions of P-glycoprotein can be induced or inhibited by some drugs So for example the induction (or stimulation) of the activityof P-glycoprotein by rifampicin (rifampin) within the lining cells of the gut causes digoxin to be ejected into the gut more vigorously This results in a fall in the plasma levels of digoxin (see lsquoDigitalis glycosides + Rifamycinsrsquo p938) In contrast verapamil appears to inhibit the activity of P-glycoprotein and is well known to increase digoxin levels (see lsquoDigitalisglycosides + Calcium-channel blockers Verapamilrsquo p916) Ketoconazole also has P-glycoprotein inhibitory effects and has been shown to increase CSF levels of ritonavir possibly by preventing the efflux of ritonavir

from the CNS (see lsquoProtease inhibitors + Azoles Ketoconazolersquo p814) Thus the induction or inhibition of P-glycoprotein can have an impact on the pharmacokinetics of some drugs Note that there is evidencethat P-glycoprotein inhibition may have a greater impact on drug distribution (eg into the brain) than on drug absorption (eg plasma levels)2 There is an overlap between CYP3A4 and P-glycoprotein inhibitors inducers and substrates Therefore both mechanisms may be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 lsquoTable 16rsquo (p8) lists some possible P-glycoprotein inhibitors and inducers Many drugs that are substrates for CYP3A4 (see lsquoTable 14rsquo (p6)) are also substrates for P-glycoprotein Digoxin and talinolol are examples of the few drugs that are substrates for P-glycoprotein but not CYP3A4

P-glycoprotein is also expressed in some cancer cells (where it was first identified) This has led to the development of specific P-glycoprotein inhibitors such as valspodar with the aim of improving the penetration of cytotoxic drugs into cancer cells1 Mizuno N Niwa T Yotsumoto Y Sugiyama Y Impact of drug transporter studies on drug discovery and development Pharmacol Rev (2003) 55 425ndash612 Lin JH Yamazaki M Clinical relevance of P-glycoprotein in drug therapy Drug Metab Rev (2003) 35 417ndash54

Table 16 Some possible inhibitors and inducers of P-glycoprotein shownto alter the levels of P-glycoprotein substrates in clinical studies1Inhibitors AtorvastatinClarithromycinDipyridamoleErythromycinItraconazoleKetoconazolePropafenoneQuinidineValspodarVerapamilInducersRifampicinSt Johnrsquos wort (Hypericumperforatum)

(a) Protein-binding interactionsFollowing absorption drugs are rapidly distributed around the body by the circulation Some drugs are totally dissolved in the plasma water but many others are transported with some proportion of their molecules in solutionand the rest bound to plasma proteins particularly the albumins The extent of this binding varies enormously but some drugs are extremely highly bound For example dicoumarol has only four out of every 1000 molecules remaining unbound at serum concentrations of 05 mg Drugs can also become bound to albumin in the interstitial fluid and some such as digoxin can bind to the heart muscle tissueThe binding of drugs to the plasma proteins is reversible an equilibrium being established between those molecules that are bound and those that are not Only the unbound molecules remain free and pharmacologically active while those that are bound form a circulating but pharmacologically inactive reservoir which in the case of drugs with a low-extraction ratio is temporarily protected from metabolism and excretion As the free molecules become metabolised some of the bound molecules become unbound and pass into solution to exert their normal pharmacological actionsbefore they in their turn are metabolised and excreted

Depending on the concentrations and their relative affinities for the binding sites one drug may successfully compete with another and displace it from the sites it is already occupying The displaced (and now active) drug molecules pass into the plasma water where their concentration rises So for example a drug that reduces the binding from 99 to 95 would

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

increase the unbound concentration of free and active drug from 1 to 5 (a fivefold increase) This displacement is only likely to raise the number of free and active molecules significantly if the majority of the drug is within the plasma rather than the tissues so that only drugs with a low apparent volume of distribution (Vd) will be affected Examples include thesulphonylureas such as tolbutamide (96 bound Vd 10 litres) oral anticoagulants such as warfarin (99 bound Vd 9 litres) and phenytoin (90 bound Vd 35 litres) However another important factor is clearance Clinically important protein-binding interactions are unlikely if only a small proportion of the drug is eliminated during a single-passage throughthe eliminating organ (low-extraction ratio drugs) since any increase in free fraction will be effectively cleared Most drugs that are extensively bound to plasma proteins and subject to displacement reactions (eg warfarin sulphonylureas phenytoin methotrexate and valproate) have lowextraction ratios and drug exposure is therefore independent of proteinbindingAn example of displacement of this kind happens when patients stabilised on warfarin are given cloral hydrate because its major metabolite trichloroacetic acid is a highly bound compound that successfully displaces warfarin This effect is only very short-lived because the now free and active warfarin molecules become exposed to metabolism as the blood flows through the liver and the amount of drug rapidly falls This transient increase in free warfarin levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor complexes that are produced when warfarin is taken have a very long half-life and thus take a long time to reach a new steady state Normally no change in the warfarin dosage is needed (see lsquoCoumarins + Cloral and derivativesrsquo p396)In vitro many commonly used drugs are capable of being displaced by others but in the body the effects seem almost always to be buffered so effectively that the outcome is not normally clinically important It would therefore seem that the importance of this interaction mechanism has been grossly over-emphasised1-3 It is difficult to find an example of a clinically important interaction due to this mechanism alone It has been suggested that this interaction mechanism is likely to be important only for drugs given intravenously that have a high-extraction ratio a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic index Lidocaine has been given as an example of a drug fitting these criteria3 Some drug interactions that were originally assumed to be due to changes in protein binding have subsequently been shown to have other interaction mechanisms involved For example inhibition of metabolism has subsequentlybeen shown to be important in the interactions between lsquowarfarin and phenylbutazonersquo (p434) and lsquotolbutamide and sulphonamidersquo (p506)However knowledge of altered protein binding is important in therapeutic drug monitoring Suppose for example a patient taking phenytoin was given a drug that displaced phenytoin from its binding sites The amount of free phenytoin would rise but this would be quickly eliminated by metabolism and excretion thereby keeping the amount of free active phenytointhe same However the total amount of phenytoin would now be reduced Therefore if phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the phenytoin is subtherapeutic and that the dose may therefore need increasing However as the amount of free active phenytoin is unchanged this would not be necessary and mayeven be dangerousBasic drugs as well as acidic drugs can be highly protein bound but clinically important displacement interactions do not seem to have been described The reasons seem to be that the binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid glycoprotein rather than albumin) and in addition basic drugs have a large Vd with only a small proportion of the total amount of drug being within the plasma

(b) Induction or inhibition of drug transport proteinsIt is increasingly being recognised that distribution of drugs into the brain and some other organs such as the testes is limited by the action of drug transporter proteins such as P-glycoprotein These proteins actively transport drugs out of cells when they have passively diffused in Drugs that are inhibitors of these transporters could therefore increase the uptake of drug substrates into the brain which could either increase adverse CNS effects or be beneficial For more information see lsquoDrug transporter proteinsrsquo (p8)

Table 12 Drugs affecting or metabolised by the cytochrome P450isoenzyme CYP1A2Inhibitors CimetidineFluoroquinolonesCiprofloxacinEnoxacinGrepafloxacinFluvoxamineIpriflavoneMexiletineRofecoxibTacrineTiclopidineZileutonInducers BarbituratesPhenytoinTobacco smokeSubstrates CaffeineClozapineDuloxetineFlecainideOlanzapine

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik

RasagilineRopiniroleTacrineTheophylline

Tizanidine

Tricyclic antidepressantsAmitriptylineClomipramineImipramineTriptansFrovatriptanZolmitriptanR-WarfarinConsidered the preferred in vivo substrates see Bjornsson TD Callaghan JT EinolfHJ et al The conduct of in vitro and in vivo drugndashdrug interaction studies a PhRMA

perspective J Clin Pharmacol (2003) 43 443ndash69

• Distribusi fase 1 hati ginjal otak dan organ-organ lain yang perfusinya baik