title: Comparison of the effects of metoclopramide and domperidone on HERG channels.
abstract: Torsades de pointes (TdP) is a potentially fatal form of ventricular arrhythmia that occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings). A likely mechanism for QT prolongation and TdP is blockade of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by HERG (human ether-a-go-go-related gene). The gastroprokinetic agent cisapride is a potent blocker of HERG currents and serious cardiac arrhythmias and deaths from TdP and ventricular fibrillation have been reported in patients taking cisapride. The aim of the present study was to compare the effects of the gastroprokinetic agents domperidone and metoclopramide on HERG channels transiently expressed in human embryonic kidney (HEK 293) cells using the whole-cell configuration of the patch-clamp technique. Both domperidone and metoclopramide concentration-dependently blocked HERG currents, and the following values were calculated for IC(50) (the concentrations causing half-maximal inhibition) and n (the Hill coefficient): 57.0 nmol/l and 0.99 for domperidone, 5.4 micromol/l and 0.95 for metoclopramide. The observation that the extent of block of HERG currents by domperidone increased at more positive membrane potentials whereas block of HERG currents by metoclopramide displayed a smaller degree of voltage dependency seems to indicate that domperidone and metoclopramide have distinct binding sites on HERG channels. In conclusion, the potency for block of HERG currents is about 100-fold lower for metoclopramide when compared to domperidone.
authors.affiliation: Federal Institute for Drugs and Medical Devices, Bonn, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Claassen
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Zünkler
mesh_terms: D000932:Antiemetics / Q000633:toxicity*; D002460:Cell Line; D004294:Domperidone / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008787:Metoclopramide / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*
chemical_list: D000932:Antiemetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; D004294:Domperidone; D008787:Metoclopramide