Interactions of the narcotic l-alpha-acetylmethadol with human cardiac K+ channels.
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.
Kang
Jiesheng
J
Drug Safety Evaluation, Aventis Pharmaceuticals Inc., Route 202-206, Building JR2-2236, Bridgewater, NJ 08807, USA.
Chen
Xiao Liang
XL
Wang
Hongge
H
Rampe
David
D
D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008692:Methadyl Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
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; D009294:Narcotics; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C020783:paracymethadol; D008692:Methadyl Acetate