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 IC₅₀ (the concentrations causing half-maximal inhibition) and n (the Hill coefficient): 57.0 nmol/l and 0.99 for domperidone, 5.4 µmol/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.

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

“…PPB are either from published data (plain text) or measured in our laboratories (bold italics). [22]; c: [23]; d: [24,25]; e: [26]; f: [27]; g: [28]; h: [19]; i: [29]; j: [30]; k: [31]; l: [32]; m: [33]; n: [34]; o: [35]; p: [36]; q: [37]; r: [38]; s: [39]; t: [40]; u: [41]; v: [42]; w: [43]; x: [44]; y: [45]; z: [46]; aa: [47]; bb: [48]; cc: [49]; dd: [50]; ee: [51]; ff: [52]; gg: [53]; hh: [54]; ii: [55]; jj: [56]; kk: [57]; ll: [58]; mm: [59]; nn: [60]; oo: [61]; pp: [62]; qq: [63]; rr: [64]; ss: [65]; tt: [66]; uu: [67]; vv: [68]; ww: …”

Effects of fluoroquinolones on HERG channels and on pancreatic β-cell ATP-sensitive K+ channels

“…An inverted Zeiss LSM-510 laser-scanning confocal imaging system with an argon laser (excitation wavelength: 488 nm) was employed and EGFP-induced fluorescence (>505 nm) was detected using a photomultiplier tube. HERG currents were recorded as described recently (Claaßen and Zünkler, 2005). HERG current signals were filtered at 2 kHz with the help of a Bessel filter (902, Frequency Devices, Haverhill, Massachusetts, USA).…”

Domperidone-Associated Sudden Cardiac Death in the General Population and Implications for Use in Patients Undergoing Hemodialysis: A Literature Review

“…18 Interestingly, one in vitro study showed that both metoclopramide and domperidone bind to and block hERG (human ether-à-go-gorelated gene) channels in a concentration-dependent manner. 19 Blockade of the hERG channel is a likely mechanism for QTc prolongation, and it has been shown that domperidone is a more potent blocker of hERG currents (by a factor of 100) than metoclopramide; however, this finding has not been confirmed in vivo.…”

“…In vitro data have suggested a concentrationdependent prolongation of the QTc interval, which in turn suggests a potential dose-response relationship. 19 Conversely, domperidone is eliminated mostly hepatically, with less than 1% renal excretion of unchanged drug. 22 Therefore, this drug does not significantly accumulate in patients with renal impairment.…”