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Effect of Clebopride, Antidopaminergic Gastrointestinal Prokinetics, on Cardiac Repolarization

Department of Pharmacology and National Research Laboratory, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea

Correspondence: Address correspondence to Eun-Joo Kim, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, 305-343, Korea. E-mail:ejkim{at}kitox.re.kr

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 µM significantly decreased the V _max 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 µM. Clebopride was found to have no effect on sodium channel currents. When these results were compared with C _max (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.

Key Words: Action Potential • Clebopride • hERG • Na⁺ Channel • QT Interval Prolongation

International Journal of Toxicology, Vol. 26, No. 1, 25-31 (2007)
DOI: 10.1080/10915810601117992


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