metabolism obat.pdf

7/25/2019 Metabolism Obat.pdf

1/24
http://www.capsugel.com/products/licaps.php


2/24

1. Menjelaskan peran hepar dalam eliminasi obat

2. Menjelaskan klasifikasi hasil metabolisme obat

3. Menjelaskan jalur reaksi metabolisme obat dan ensim

yang terlibat4. Menjelaskan sumber variasi metabolisme obat

5. Memprediksi perubahan klirens akibat adanya interaksi

pada metabolisme obat
http://www.capsugel.com/products/licaps.php


3/24

Perfusi Liver:

Hepatic artery

Hepatic portal vein(vena porta)

Peranvena hepatica ?


4/24

Peran hepar dalam

metabolisme obat ?


5/24

Drug MetaboliteEnzyme

Metabolisme obat adalah ..............................................................

..........................................................................................................

..........................................................................................................

..........................................................................................................

......................................................................


6/24

No Drug Metabolite

1 Active Inactive

2 Active Active

3 Inactive Active

4 Active Reactive Intermediate

Contoh

Reaksi ?


7/24

Aciclovir:is poorly absorbed from the gastrointestinal tract after oral

dose. Bioavailability of oral aciclovir is about 10 to 20%; orally

active prodrugssuch as valciclovirhave been developed to

overcome this poor absorption.

Pertanyaan:

Bagaimana valciclovir dapat bekerja sebagai prodrugs ?

Valciclovir: is readily absorbed from the gastrointestinal tract

after oral doses, and rapidly converted to aciclovir and valine byfirst-pass intestinal or hepatic metabolism.


8/24

Reaksi Fase I:

Reaksi fase I adalah reaksi .............................................

Tipe reaksi & ensim yang terlibat:1. ...................................................................................

2. ...................................................................................

3. ...................................................................................


9/24

Reaksi Fase II:

Reaksi fase II adalah reaksi

...............................................

Tipe reaksi & ensim yang terlibat:

1. ......................................................................................

2. ......................................................................................

3. ......................................................................................

4. ......................................................................................


10/24

The MFOs System


11/24

Salicylic acidSalicylacyl

glucuronideSalicylurea

Genticyl urate GentisateSalicyl phenolic

glucuronide

Sulphates conjugates

gentisate

Glucuronide conjugates

gentisate


12/24
http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+codeine&source=images&cd=&cad=rja&docid=4spp6u3fMzJUzM&tbnid=obfbWNt4fD3cqM:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S037907381000349X&ei=_KU_Ucj8Ea-eiAft8oC4DA&bvm=bv.43287494,d.bmk&psig=AFQjCNEYSU-qouIhjMOQJALt2nmR63LKTg&ust=1363212126143364


13/24

Paracetamole is very safe provided in the normal

therapeutic dose. However after overdoses (8-10 g), fatal

liver damage can results.

Paracetamole is metabolized mainly by conjugation withsulphate and glucuronic acid ( 90-95%).

Only a minor proportion is metabolized by oxidation

which is catalysed by cytochrome P450. This producesa metabolite which is toxic but normally detoxified by

reaction with glutathione.
http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554


14/24

GSH

Reactive

intermediate

N-acetyl

systeine

Metabolisme Paracetamol
http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554


15/24

1. Faktor genetik

2. Kondisi fisologis

3. Faktor lingkungan & Interaksi obat4. Regimen dosis

Intrinsic

Clearance


16/24

Variasi genetik pada cytochrome P-450 (CYP) isozymes

Kasus:

Rapid acetylatorsvs Slow acetylators pada asetilasi

isoniazide (Evans et al, 1968)

EM (Efficient Metabolizer) vs PM (Poor Metabolizer)

phenytoin pada 4% subjek caucasian & 16% subjek di

Jepang (Wilkinson et al, 1998)


17/24

1. Usia

2. Gender

3. Diet/Nutrisi

4. Patofisiologi


18/24

Age Metabolism Capacity Development

Birth Sulfatation

1st

week Reduction, Oxidation

1stmonth Acetylation

2ndmonth Glucuronidation

3thmonth Glycine, Glutathione, & Cystein Conjugation

Children

are not

little adults


19/24

Rute pemberian obat

hepatic first-pass effect

Dose-dependent (non-linear)

pharmacokinetics

2

1


20/24

1. Induksi Ensim (Inducer)

2. Inhibisi Ensim (Inhibitor)

Intrinsic Clearance

Hepar


21/24

Inducer Induced Drugs

Carbamazepin Paracetamol; Phenytoin; Warfarin

Griseofulvin; Haloperidol;

Meprobamat*)Warfarin

Phenytoin Cortisol; Digitoxin; Phenobarbital

Phenobarbital*) Chloramphenicol; Cortisol,eDexamethazon; Digitoxin; Estradiole;

Griseofulvin; Phenytoin; Progesteron;

Testoteron; Tolbutamid

Rifampicin*)

Estrogen; Methadon; Phenobarbital;Prednisolon; Saquinavir; Warfarin

*) auto-inducer


22/24

Inducer:

Benzopyrene(asap rokok)

Chlordane(insektisida)

3-methyl-cholantrene(polycyclic hydrocarbons)

Laju eliminasi theophylline meningkat pada perokok

induksi ensim oleh benzopyrene


23/24

Inhibitors Inhibited Drugs

Cimetidine Phenytoine; Theophylline; Warfarine

Erythromycine Carbamazepien

Fluoxetine Imipramine; Desipramine

MeperidinePromazine

Kontrasepsi oral

Phenytoine Bishydrocoumarine; Chloramphenicole,

Cycloserine, Isoniazide, Sulpha

Tolbutamide Chloramphenicole, Phenylbutazone,

Sulpha, Probenecide, Ethanol


24/24

Bioflavonoid:Naringin (bioflavonoid - grapefruit juice) menghambat

CYP 3A4 meningkatkan AUC Coumain, Cyclosporin,

Felodipin, Midazolam, Saquinavir etc

Penurunan intake asam lemak:

menurunkan aktivitas sistem MFO

Carbon monoxide, Heavy metals:

menghambat aktivitas ensim hepatik

metabolism obat.pdf

Documents