Interactions of the narcotic l-alpha-acetylmethadol with human cardiac K+ channels.

Abstract	l-alpha-acetylmethadol is a long-acting narcotic analgesic that is used in the treatment of opiate addiction. However, the drug has been associated with cases of QT interval prolongation and ventricular arrhythmia. To understand the mechanism underlying these clinical findings, we examined the effects of l-alpha-acetylmethadol on the cloned human cardiac K(+) channels HERG (human ether-a-go-go-related gene), KvLQT1/minK and Kv4.3. Using patch clamp electrophysiology, we found that l-alpha-acetylmethadol inhibited HERG channel currents in a voltage-dependent manner displaying an IC(50) value of 3 microM. The major active metabolite of l-alpha-acetylmethadol, noracetylmethadol, inhibited HERG with an estimated IC(50) values of 12 microM. l-alpha-acetylmethadol had little or no effect on Kv4.3 or KvLQT1/minK K(+) channel currents at concentration up to 10 microM. We conclude that the proarrhythmic effects of l-alpha-acetylmethadol are due to specific blockade of the HERG cardiac K(+) channel and that its active metabolite noracetylmethadol may provide a safer alternative in the treatment of opiate addiction.
Authors	Jiesheng Kang, Xiao Liang Chen, Hongge Wang, David Rampe
Journal	European journal of pharmacology (Eur J Pharmacol) Vol. 458 Issue 1-2 Pg. 25-9 (Jan 01 2003) ISSN: 0014-2999 [Print] Netherlands
PMID	12498903 (Publication Type: Journal Article)
Chemical References	Cation Transport Proteins DNA-Binding Proteins ERG protein, human ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels KCNH2 protein, human KCNH6 protein, human Narcotics Potassium Channels Potassium Channels, Voltage-Gated Trans-Activators Transcriptional Regulator ERG paracymethadol Methadyl Acetate
Topics	Animals CHO Cells Cation Transport Proteins Cricetinae DNA-Binding Proteins Dose-Response Relationship, Drug ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Humans Membrane Potentials (drug effects) Methadyl Acetate (analogs & derivatives, pharmacology) Narcotics (pharmacology) Potassium Channels (genetics, physiology) Potassium Channels, Voltage-Gated Trans-Activators Transcriptional Regulator ERG

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