title: Additive effects of combined application of multiple hERG blockers.
abstract: Pro-arrhythmia by noncardiac drugs has become an important safety concern in the pharmaceutical industry. The most common underlying mechanism for induction of arrhythmias by noncardiac drugs is off-target block of the native cardiac repolarizing current, I Kr. The pore-forming subunit of I Kr is encoded by the human ether-a-go-go related gene (hERG), and in vitro measurements of hERG activity has become a standard component of drug safety evaluations. hERG/I Kr channels are blocked by a wide array of different chemical series; therefore, patients could be exposed to multiple blockers. There are few published studies addressing whether multiple blockers will exert independent actions on hERG channels. Whole cell patch clamp was used to evaluate the potential for cooperative effects when 2 hERG blocking agents were applied simultaneously. Cisapride, quinidine, fluvoxamine, and BeKm-1 were selected as representative agents binding to: (1) hydrophobic residues in the inner vestibule (cisapride and quinidine, the most frequent sites of interaction), (2) an extracellular segment near the pore (BeKm-1) or, (3) an unknown site (fluvoxamine). No synergistic blocking actions were seen. In some cases block was slightly less than additive. On balance, the results are consistent with additive and independent actions with simultaneous application of 2 hERG blockers.
authors.affiliation: Department of Neurobiology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Margulis
authors.forename: Steve
authors.initials: S
authors.lastname: Sorota
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D020117:Cisapride / Q000494:pharmacology; D004357:Drug Synergism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018408:Patch-Clamp Techniques; D011802:Quinidine / Q000494:pharmacology; D012604:Scorpion Venoms / Q000494:pharmacology
chemical_list: C425305:BeKm-1 toxin; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D012604:Scorpion Venoms; D011802:Quinidine; D016666:Fluvoxamine; D020117:Cisapride