title: Characterization of the inhibitory effects of erythromycin and clarithromycin on the HERG potassium channel.
abstract: Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans, however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking. The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current (IKr) encoded by HERG (the human ether-a-go-go-related gene) at drug concentrations, temperature and ionic conditions mimicking those occurring in human subjects. Potassium currents in HEK 293 cells stably transfected with HERG were recorded using a whole cell voltage clamp method. Exposure of cells to erythromycin reduced the HERG encoded potassium current in a concentration dependent manner with an IC50 of 38.9 +/- 1.2 microM and Hill Slope factor of 0.4 +/- 0.1. Clarithromycin produced a similar concentration-dependent block with an IC50 of 45.7 +/- 1.1 microM and Hill Slope factor of 1.0 +/- 0.1. Erythromycin (25-250 microM) and clarithromycin (5 or 25 microM) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol. The results of this study document that both erythromycin and clarithromycin significantly inhibit the HERG potassium current at clinically relevant concentrations.
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112-2699, USA.
authors.forename: Scott J C
authors.initials: SJ
authors.lastname: Stanat
authors.forename: Carol G
authors.initials: CG
authors.lastname: Carlton
authors.forename: William J
authors.initials: WJ
authors.lastname: Crumb
authors.forename: Krishna C
authors.initials: KC
authors.lastname: Agrawal
authors.forename: Craig W
authors.initials: CW
authors.lastname: Clarkson
mesh_terms: D000200:Action Potentials; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D017291:Clarithromycin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D004917:Erythromycin / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D013696:Temperature; D014162:Transfection
chemical_list: D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D018942:Macrolides; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D004917:Erythromycin; D017291:Clarithromycin