Benoit Drolet, Guy Rousseau, Pascal Daleau, René Cardinal and Jacques TurgeonTreatment of Gastrointestinal Motility Disorders

Domperidone Should Not Be Considered a No-Risk Alternative to Cisapride in the

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Domperidone Should Not Be Considered a No-RiskAlternative to Cisapride in the Treatment of

Gastrointestinal Motility DisordersBenoit Drolet, MSc; Guy Rousseau, PhD; Pascal Daleau, PhD; Rene Cardinal, PhD; Jacques Turgeon, PhD

Background—Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with domperidone,a gastrokinetic and antiemetic agent available worldwide but still under investigation in the United States. Althoughelectrolyte disturbances such as hypokalemia could account for some of these events, we hypothesized that domperidonemay have unsuspected electrophysiological effects predisposing some patients to proarrhythmia.

Methods and Results—Studies were undertaken in 9 isolated guinea pig hearts, which demonstrated reverse use–dependentprolongation of cardiac repolarization by 100 nmol/L domperidone. Action potential duration increased 27% from baselinewith domperidone (from 11463 to 14562 ms) during pacing at a cycle length of 250 ms, and a 9% increase (from 9762 to10663 ms) was seen with pacing at a cycle length of 150 ms. Experiments in human ether-a-go-go–related gene(HERG)-transfected Chinese hamster ovary cells (n532) demonstrated a concentration-dependent block of the rapidcomponent (IKr) of the delayed rectifier potassium current. The tail current decreased by 50% at 162 nmol/L domperidone.

Conclusions—Domperidone possesses cardiac electrophysiological effects similar to those of cisapride and class III antiarrhyth-mic drugs. These effects are observed at clinically relevant concentrations of the drug. Therefore, domperidone should not beconsidered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market.(Circulation.2000;102:1883-1885.)

Key Words: arrhythmian ion channelsn torsade de pointesn electrophysiologyn long-QT syndrome

Domperidone (Motilium) has been marketed worldwidesince 1978, but it is still under investigation in the

United States. It is a unique compound that has both gastro-kinetic and antiemetic activities. Chemically distinct fromcisapride, domperidone is a peripheral dopamine2-receptorantagonist that might seem to be an attractive, safer alterna-tive to cisapride, a drug that was recently withdrawn from theUS market due to drug-related proarrhythmic events.1–3

However, QT prolongation, life-threatening ventriculartachyarrhythmias, and even cardiac arrests have also beenreported after the use of domperidone.4–11 It was generallyassumed that these adverse effects were related to an underlyingelectrolytic disturbance, eg, hypokalemia, and not to a specificdrug effect.5,7–9

We investigated whether unexpected electrophysiological ef-fects of domperidone on cardiac repolarization might alsoprovide an explanation for some of the observed proarrhythmicevents. Therefore, we determined the action potential–prolong-ing effects of domperidone in isolated hearts and characterizedthe effects of the drug on a major cardiac potassium current (IKr)using the whole-cell patch-clamp technique.

MethodsExperiments were performed in accordance with our institutionalguidelines on animal use in research. Animals were housed andmaintained in compliance with theGuide to the Care and Use ofExperimental Animalsof the Canadian Council on Animal Care.

Experiments With Isolated HeartsExperiments with isolated guinea pig hearts were performed asdescribed previously.12 The hearts were perfused with Krebs-Henseleit buffer during a control period of 10 minutes; this wasfollowed by 15 minutes of perfusion with buffer containing 100nmol/L domperidone dissolved in 1 mL of DMSO. Perfusion withbuffer containing no drug was then restarted during a 10-minutewashout period. The same concentration of DMSO (0.1% v/v) wasalso present in baseline and washout buffer solutions. Monophasicaction potentials from the left ventricle were recorded by a pressure-maintained catheter every 60 s for a 3-s period at basic pacing cyclelengths (BCL) of 250, 200, and 150 ms.

Patch-Clamp ExperimentsExperiments were performed on HERG-transfected Chinese hamsterovary (CHO) cells. Preparation and harvesting of the CHO cells weredone as described previously.13 Membrane currents were recorded inwhole cell configuration using suction pipettes. The composition ofthe superfusion and internal pipette solutions was also described

Received June 23, 2000; revision received August 22, 2000; accepted August 23, 2000.From the Institut de cardiologie de Quebec, Hopital Laval (B.D., P.D., J.T.) et Facultes de Pharmacie (B.D., J.T.) et de Medecine (P.D.), Universite Laval,

Sainte-Foy, Quebec, Canada, and the Centre de Recherche, Hopital du Sacre-Cœur de Montre´al (G.R., R.C., J.T.), Departement de Pharmacologie, Faculte´ deMedecine (G.R., R.C., J.T.) et Faculte de Pharmacie (J.T.), Universite de Montreal, Montreal, Quebec, Canada.

Correspondence to Jacques Turgeon, PhD, Dean, Faculty of Pharmacy, University of Montreal, CP 6128 succursale Centre-ville, Montreal QC Canada H3C3J7. E-mail jacques.turgeon@umontreal.ca

© 2000 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org

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previously.14 Domperidone solutions of 30 nmol/L to 1mmol/L wereprepared daily by dissolving the required amounts of the drug in 100mL of DMSO. The same concentration of DMSO (0.1% v/v) wasalso present in baseline and washout buffer solutions. All voltage-clamp experiments were performed at 22°C to 23°C.

Statistical AnalysisData are presented as mean6SEM. The magnitude of domperidoneeffects for isolated heart data were analyzed with Student’s pairedttest. In the patch-clamp experiments, the concentration-dependentblock of the HERG tail current was tested by Hotelling’sT2-test.P,0.05 was considered statistically significant.

ResultsExperiments With Isolated HeartsExamples of monophasic action potentials recorded at baseline andduring perfusion with 100 nmol/L domperidone at a BCL of 250 msare illustrated in Figure 1A. Experiments in isolated hearts (n59)showed an increase in monophasic action potential duration mea-sured at 90% repolarization (MAPD90) during perfusion withdomperidone (Figure 1B). At a BCL of 250 ms, MAPD90 increasedfrom 11463 ms at baseline to 14562 ms after 15 minutes of drugperfusion (P,0.05); it then decreased back to 13662 ms after 10minutes of washout (P,0.05 versus domperidone). At a BCL of200 ms, MAPD90 increased from 11062 ms at baseline to 13063ms after 15 minutes of drug perfusion (P,0.05); it decreased backto 11863 ms after 10 minutes of washout (P,0.05 versus domp-eridone). Finally, at the shortest BCL of 150 ms, MAPD90 increased

from 9762 at baseline to 10663 ms after domperidone perfusion(P,0.05), and it returned to baseline levels after washout (9964ms). Thus, domperidone was associated with a 27% increase inMAPD90 at the longest BCL and with a 9% increase at the shortestBCL. Such reverse use–dependent characteristics are typically seenwith IKr blockers.

Patch-Clamp ExperimentsThe mechanism underlying the action potential–prolonging ef-fects of domperidone was investigated by conducting patch-clamp experiments in CHO cells. Figure 2A shows the currentselicited in a HERG-transfected CHO cell perfused under controlconditions (baseline), after 15 minutes of 300 nmol/L domperi-done, and after a 20-minute washout period. In this cell, 300nmol/L domperidone caused a 59% reduction of the tail current.Similar experiments were conducted in a total of 32 cells(n58/concentration). The block of tail currents was assessedwith domperidone concentrations ranging from 30 nmol/L to1 mmol/L, and the data were fitted to the Hill equation, whichgave an estimated IC50 of 162 nmol/L (Figure 2B). The decreasein the tail current was 1266% at 30 nmol/L, 3564% at 100nmol/L, 6564% at 300 nmol/L, and 9561% at 1mmol/L.

Figure 1. A, Monophasic action potential signals recorded atbaseline and after 15 minutes of 100 nmol/L domperidone at aBCL of 250 ms. B, Serial changes in MAPD90 at BCLs of 250, 200,and 150 ms in hearts (n59) sequentially perfused with buffer atbaseline, 100 nmol/L domperidone, and washout buffer.

Figure 2. A, Activating and tail currents elicited by a 4-s step to 20mV in a HERG-transfected CHO cell under control conditions (base-line), after 15 minutes of perfusion with 300 nmol/L domperidone, andafter a 20-minute washout period. B, HERG tail current amplitude,measured at 20 mV in CHO cells (n532) and normalized to control,plotted as a function of domperidone concentration.

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DiscussionOur results indicate that domperidone can prolong cardiacrepolarization in a reverse rate–dependent manner by block-ing IKr. In fact, we showed that 100 nmol/L domperidonecaused a significant prolongation of cardiac repolarization('25% to 30%). Excessive IKr block may lead to triggeredtachyarrhythmias and sudden death.15 These results provide anew explanation for QT prolongation and ventriculartachyarrhythmia during domperidone treatment.

An inhibition of the HERG current was demonstrated in CHOcells. The estimated IC50 for IKr was 162 nmol/L. Pharmacoki-netic studies showed that the mean plasma concentration ofdomperidone in healthy subjects is 21 ng/mL (49 nmol/L) after14 days of domperidone at a dose of 30 mg/d, which was similarto the mean plasma concentration of 18 ng/mL (42 nmol/L)observed after the first dose.16 However, the mean maximalconcentration values achieved 30 minutes after 10 and 60 mgoral doses of domperidone were 23 and 80 ng/mL (54 and 188nmol/L), respectively.17 Therefore, a reduction of the IKr currentand delayed cardiac repolarization are expected to be seen inpatients treated with the recommended doses of domperidone(10 to 20 mg TID/QID).

Similar electrophysiological properties have been extensivelydescribed recently with cisapride, another gastrokinetic drug. Thisdrug had to be withdrawn from the US market due to unacceptablecardiac toxicity.2,3,12 Because cisapride was one of the overallmost-prescribed drugs in the United States and definitely the mostprescribed in its therapeutic class, its withdrawn will cause a rapidshift toward alternative therapies.

With both gastrokinetic and antiemetic activities, domperidoneprovides short-term relief of dyspepsia, diabetic gastroparesis, orgastroesophageal reflux, and it prevents the nausea and vomitingassociated with chemotherapy and antiparkinsonian drugs.1

Unlike metoclopramide, another prokinetic dopamine-receptorantagonist, domperidone does not readily cross the blood-brainbarrier, and reports of adverse effects on the central nervous system,such as dystonic reactions, are rare.1 Moreover, in the managementof diabetic gastropathy, domperidone’s antiemetic activity distin-guishes it from cisapride.

Because of its “apparent” favorable safety profile, domperi-done might seem to be an appealing, safer alternative tocisapride. In view of the present findings and consideringprevious reports on domperidone cardiac toxicity,4–11this shouldnot be the case. Clinical attention should be directed toward QTprolongation and proarrhythmic events when domperidone isadministered, as it was with cisapride. Because domperidone canblock IKr, caution is also needed during coadministration withother IKr blockers, like class III drugs and other compounds suchas antimicrobials, antihistamines, and neuroleptics.18–21 Domp-eridone should be one of the next compounds to add to thegrowing list of drugs associated with acquired long-QTsyndrome.

ConclusionsDomperidone is a potent IKr blocker. It prolongs cardiacrepolarization at clinically relevant drug concentrations, andit should not be considered a no-risk alternative to cisapride.Therefore, clinical attention to QT prolongation and triggeredventricular tachyarrhythmias should be warranted when pre-

scribing domperidone, particularly in patients with hepatic orrenal insufficiency, in those who suffer from long-QT syn-drome, and in patients on multidrug regimens.

AcknowledgmentsThis study was supported by the Medical Research Council of Canada(grant MT-11876) and the Heart and Stroke Foundation of Quebec. B.Drolet is the recipient of studentships from the Heart and Stroke Foundationof Canada and from the Fonds pour la Formation de Chercheurs et l’Aidea la Recherche (FCAR). Dr Rousseau is the recipient of a scholarship fromthe MRC/Canadian Hypertension Society. Dr Daleau is the recipient of ascholarship from the Fonds de la Recherche en Sante du Quebec (FRSQ).Dr Turgeon was the recipient of a scholarship from the Joseph C. EdwardsFoundation. The authors also thank Michel Blouin, Lynn Atton, andChantal de Montigny for technical assistance.

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Drolet et al Domperidone Blocks Cardiac IKr 1885

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