title: Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics.
abstract: Several macrolides have been reported to cause QT prolongation and ventricular arrhythmias such as torsades de pointes. To clarify the underlying ionic mechanisms, we examined the effects of six macrolides on the human ether-a-go-go-related gene (HERG)-encoded potassium current stably expressed in human embryonic kidney-293 cells. All six drugs showed a concentration-dependent inhibition of the current with the following IC(50) values: clarithromycin, 32.9 microM; roxithromycin, 36.5 microM; erythromycin, 72.2 microM; josamycin, 102.4 microM; erythromycylamine, 273.9 microM; and oleandomycin, 339.6 microM. A metabolite of erythromycin, des-methyl erythromycin, was also found to inhibit HERG current with an IC(50) of 147.1 microM. These findings imply that the blockade of HERG may be a common feature of macrolides and may contribute to the QT prolongation observed clinically with some of these compounds. Mechanistic studies showed that inhibition of HERG current by clarithromycin did not require activation of the channel and was both voltage- and time-dependent. The blocking time course could be described by a first-order reaction between the drug and the channel. Both binding and unbinding processes appeared to speed up as the membrane was more depolarized, indicating that the drug-channel interaction may be affected by electrostatic responses.
authors.affiliation: Department of General Pharmacology, Groton Laboratories, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Volberg
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Koci
authors.forename: Weiguo
authors.initials: W
authors.lastname: Su
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins; D002460:Cell Line; D017291:Clarithromycin / Q000494:pharmacology; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D000900:Anti-Bacterial Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D017291:Clarithromycin