title: Interactions at human ether-à-go-go-related gene channels.
abstract: Several noncardiovascular drugs have the potential to induce Torsades de Pointes cardiac arrhythmias via blockade of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by human ether-à-go-go-related gene (hERG). The aim of the present study was to characterize possible interactions between terfenadine, binding to a site located inside the central cavity, and the following substances with various binding sites: dofetilide, fluvoxamine, chlorobutanol, and a hERG-specific toxin isolated from scorpion venom (CnErg1). The whole-cell configuration of the patch-clamp technique was employed on hERG channels stably expressed in human embryonic kidney 293 cells. Terfenadine does not interact with dofetilide or fluvoxamine at hERG channels. Slight subadditive inhibitory effects on hERG peak tail currents were observed when terfenadine and CnErg1 were administered in combination. Terfenadine and chlorobutanol synergistically inhibit hERG peak tail currents and enhance each other's inhibitory effect in a concentration-dependent way. In conclusion, terfenadine interacts with CnErg1 and chlorobutanol, but not with dofetilide or fluvoxamine, at hERG channels. It is shown that interactions between chlorobutanol and a hERG channel blocker binding inside the central cavity (terfenadine) produce synergistic effects on hERG currents.
authors.affiliation: Federal Institute for Drugs and Medical Devices, D-53175 Bonn, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Friemel
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Zünkler
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002724:Chlorobutanol / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D012604:Scorpion Venoms / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology*
chemical_list: D004338:Drug Combinations; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D039563:Histamine H1 Antagonists, Non-Sedating; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D012604:Scorpion Venoms; D013449:Sulfonamides; C118951:ergotoxin, Centruroides noxius; D016593:Terfenadine; D002724:Chlorobutanol; D016666:Fluvoxamine; C063533:dofetilide