Effect of clebopride, antidopaminergic gastrointestinal prokinetics, on cardiac repolarization.
The inhibition of the potassium current I(Kr) and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. In this study, the authors investigated the cardiac electrophysiological effects of clebopride, a class of antidopaminergic gastrointestinal prokinetic, that has been reported to prolong the QT interval by using the conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch clamp techniques in human ether-à-go-go-related gene (hERG)-stably transfected Chinese hamster ovarian (CHO) cells. Clebopride at 10 microM significantly decreased the Vmax of phase 0 depolarization (p < .05) and significantly prolonged the action potential duration at 90% repolarization (APD90) (p < .01), whereas the action potential duration at 50% repolarization (APD50) was not prolonged. For hERG potassium channel currents, the IC50 value was 0.62 +/- 0.30 microM. Clebopride was found to have no effect on sodium channel currents. When these results were compared with Cmax (1.02 nM) of clinical dosage (1 mg, [p.o.]), it can be suggested that clebopride is safe at the clinical dosage of 1 mg from the electrophysiological aspect. These findings indicate that clebopride, an antidopaminergic gastrointestinal prokinetic drug, may provide a sufficient "safety factor" in terms of the electrophysiological threshold concentration. But, in a supratherapeutic concentration that might possibly be encountered during overdose or impaired metabolism, clebopride may have torsadogenic potency.
Kim
Ki-Suk
KS
Department of Pharmacology and National Research Laboratory, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea.
Shin
Won-Ho
WH
Park
Sang-joon
SJ
Kim
Eun-Joo
EJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018492:Dopamine Antagonists / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D014162:Transfection
D001549:Benzamides; D018492:Dopamine Antagonists; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents; C000606913:KCNH2 protein, human; D015222:Sodium Channels; C014417:clebopride