In this issue of the Journal, Luc M. Hondeghem reports on the risk of sudden cardiac death with the use of the dopamine receptor blocker, domperidone. His article contains 3 following parts: (1) confirmatory studies to demonstrate block of the rapid component of the delayed rectifier potassium current (IKr; HERG) by domperidone; (2) reports on 5 population-based studies showing an increase in the odds ratio for sudden cardiac death in patients treated with domperidone; and (3) comments on studies suggesting poor gastrointestinal benefits associated with the use of domperidone.
Block of IKr (HERG) by domperidone was first demonstrated in 2000, when the drug was considered to be “the” alternative to cisapride for treating gastrointestinal disorders.1 Indeed, at the time, several regulatory agencies had just restricted the use of cisapride or removed it from the market because of drug-induced long QT syndrome (LQTS), torsades de pointes, and sudden cardiac death.2 Domperidone was a proposed alternative to cisapride even though several reports had already seemed indicating the same potential side effects and risk with it.3–8 Using in vitro systems, we showed that domperidone has cardiac electrophysiological effects similar to those of cisapride, although the inhibitory constant for block of IKr was 10-fold lower for cisapride (14 nM) than for domperidone (150 nM).1,9 The recent studies of Hondeghem—with longer equilibration times, longer cycle lengths, and a different animal model—suggest that the IC50 for block of IKr by domperidone is even lower in the range of 57 nM.10
Hondeghem rightly notes in his article that an IC50 for block of IKr becomes relevant if plasma concentrations can reach or approach this concentration. For instance, pharmacokinetic studies with domperidone suggest that plasma levels reach 50–120 nM after a 10 or 20 mg oral dose of domperidone.11–13 Hence, the safety margin with this drug looks rather small and would predict significant QT prolongation and proarrhythmic events in almost all patients treated with domperidone. The same is also true for other QT prolonging drugs with similar safety margins such as terfenadine, astemizole, cisapride, or moxifloxacin.9,14–16 In reality, however, this is not observed clinically. Indeed, an estimate of 1:120,000 patients experience drug-induced torsades de pointes and observed QT prolongation is in the range of 5–10 ms, a value almost undetectable in clinical practice.17,18 In this light, other factors should also be considered when estimating the risk of LQTS with orally administered drugs.
The first factor is drug bioavailability. Domperidone has a bioavailability of 17%, indicating that only a fraction of the dose reaches the systemic circulation.19 But, under conditions of complete inhibition of drug metabolism during the first pass (intestine and liver), plasma concentrations (Cmax) of domperidone could rise up to 6-fold. Under these conditions, Cmax could be as high as 300–600 nM after a 10 or 20 mg dose.
The second factor is domperidone metabolism. We and others conducted drug metabolism studies and demonstrated that CYP3A4 and CYP3A5 are the major enzymes involved in the metabolism of domperidone in the liver.20–22 These enzymes control access of the drug to the systemic circulation and determine its residence time. Coadministration of potent CYP3A inhibitors such as clarithromycine or ketoconazole have been shown to increase domperidone plasma Cmax, thus increasing the risk of LQTS.22–24
The third factor is the intracellular concentration of domperidone—or QT-prolonging drugs—in cardiac myocytes.25 It needs to be recalled that binding to the IKr channel in cardiac myocytes occurs from the intracellular site of the plasma membrane.26–28 The most relevant concentration is the intracellular concentration not the plasma concentration. Hence, the relevant question to ask is as follows: What are the factors that can determine or regulate the intracellular concentration of domperidone? Hondeghem again rightly considered the free fraction of the drug to calculate a safety margin of about 2.5. This calculation assumes that only passive diffusion occurs and that the intracellular concentration of domperidone is in equilibrium with the free plasma concentration. Our group has reported on the expression of several influx and efflux transporters in the heart.29 Of interest, human cardiac myocytes express efflux transporters such as breast cancer related protein (ABCG2) that regulate the intracellular concentration of drugs and block of IKr for QT-prolonging drugs.30 Domperidone is a likely substrate of efflux transporters, and we could assume that its free intracardiac concentration is lower than its free plasma concentration. This is a protective mechanism preventing drug access for its binding to IKr. However, under conditions of decreased efflux transporter activity (drug–drug interactions or genetic polymorphisms), the intracellular concentration of domepridone can augment and lead to significantly increased QT prolongation.
Our group has also reported on the expression (messenger RNAs) of CYP450s in human cardiac myocytes.31 In the largest cohort of human ventricular tissues ever analyzed, we reported the expression of CYP2J2, CYP2E1, and CYP2C9 at high levels. No CYP3As could be detected. These isozymes show extensive metabolic activities with intrinsic clearance values similar to those measured in the liver. Of interest, we and others showed that several CYP3A substrates are metabolized by CYP2J2 in the heart.31–33 In particular, we have shown that domperidone is extensively metabolized by CYP2J2, preventing the intracellular accumulation of the drug and binding to IKr. CYP2J2 is an isozyme which is also inhibited by ketoconazole. Thus, the same drug–drug interactions that could lead to CYP3A inhibition in the liver and to increased domperidone plasma levels could also lead to CYP2J2 inhibition in the heart and to increased domperidone intracardiac free concentration with significant block of IKr and QT prolongation.
Taken all together, these concepts and results suggest that patients treated with domperidone are at an increased risk of drug-induced long QT syndrome as follows: domperidone has a high affinity for IKr and a low safety margin. This major side effect would manifest itself under conditions of increased plasma levels (inhibition of liver CYP3As) and increased intracardiac concentrations (decreased transporter activities and/or CYP2J2 activity) allowing significant block of IKr from the intracellular site of cardiac myocytes. Drug–drug interactions, genetic and environment factors ultimately establishing the free intracellular concentration of domperidone at the vicinity of its binding site on IKr determine patients at risk of exhibiting the unwanted effects (Fig. 1).
The second, very interesting aspect of Hondeghem article is his analysis of population-based studies. He reviews 5 large population-based studies with oral domperidone and calculates an average odds ratio for sudden cardiac death of 3.63 ± 0.68. Although this average number was not obtained through a real meta-analysis strategy, he notes “that all 5 population studies detected a significant increase in sudden cardiac death is quite worrisome, as epidemiological studies are notoriously ineffective to detect such liability, even for drugs known to prolong the QTc interval and to posses proarrhythmic liabilities.”34,35 In support of this comment, Walker et al36 could not detect any significant deleterious effects of cisapride in a large epidemiological study. To our view, this is mostly explained by the fact that (1) QT is not routinely monitored in clinical practice, (2) patients experiencing proarrhythmic events are generally outside of an hospital setting, (3) the event is sudden and unpredictable, and (4) the extent of QT prolongation under nonproarrhythmic conditions is small (5–10 ms).17
Finally, Hondeghem points to the limited benefits associated with domperidone use for gastrointestinal disturbances. Although this situation is troublesome, the use of domperidone for stimulating lactation in women is even more worrisome. He points out that this indication is unapproved in Belgium, which is not the case in Canada where it is part of the monograph. Considering that drug-induced LQTS occurs mostly (70%) in women,37 the use of a low safety margin drug such as domperidone in a non–life-threatening condition is even more worrisome.
In conclusion, the Food and Drug Administration has adopted a clear position toward domperidone, a drug that has limited benefits with high risk of sudden cardiac death. Other regulatory agencies should also rapidly reconsider their position toward this drug as cases of proarrhythmias have been reported since 1984, the electrophysiological mechanism has been known since 2000, and the evidence for increased risk for sudden cardiac death with domperidone has been highly suggestive since 2005.
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