title: The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block.
abstract: Drug-induced delayed cardiac repolarization is a recognized risk factor for proarrhythmia and is associated with block of IKr (the potassium current encoded by the human ether-a- go-go-related gene [hERG]). To evaluate the utility of 2 in vitro assays widely used to assess delayed repolarization, we compared the effects of haloperidol and 9 structurally diverse drugs in a hERG and repolarization (canine Purkinje fiber action potential duration [APD]) assay over wide concentrations. Despite potent hERG current block (IC50 = 0.174 microM), haloperidol elicited a bell-shaped concentration-response relationship for APD prolongation, with lesser prolongation (and reduced plateau height) observed with concentrations eliciting maximal hERG block, consistent with multi-channel block at higher concentrations. Consistent with this hypothesis, APD prolongation with the specific IKr blocker dofetilide was a) reduced by concomitant administration of nifedipine (calcium current block) and b) reversed by lidocaine (late sodium current block). Additional studies demonstrated prominent (>50%) hERG inhibition with most (9/10) drugs despite wide APD changes (158% prolongation - 16% shortening), consistent with multi-channel block. The poor correlation between hERG and repolarization assays suggests that the hERG assay oversimplifies drug effects on the complex repolarization process for drugs demonstrating multi-channel block and that neither assay alone adequately predicts proarrhythmic risk.
authors.affiliation: Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6119, USA.
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Martin
authors.forename: Jeff S
authors.initials: JS
authors.lastname: McDermott
authors.forename: Heinz J
authors.initials: HJ
authors.lastname: Salmen
authors.forename: Jason
authors.initials: J
authors.lastname: Palmatier
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Gary A
authors.initials: GA
authors.lastname: Gintant
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004285:Dogs; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011690:Purkinje Fibers / Q000187:drug effects; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D002121:Calcium Channel Blockers; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D006220:Haloperidol