Influence of Opioid Agonists on Cardiac Human Ether-a-go-go-related Gene K+ Currents

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Abstract
We have evaluated the ability of various opioid agonists, including methadone, l-α-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K+current (IHERG) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of IHERG, with IC50 values in the 1 to 10 μM range. The other drugs tested were far less potent with respect to IHERG inhibition. Compared with the reported maximal plasma concentration (Cmax) after administration of therapeutic doses of these drugs, the ratio of IC50/Cmax was highest for codeine and morphine (>455 and >400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of IHERG. In contrast, the lowest ratios of IC50/Cmax were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of IHERG was rapid, with steady-state inhibition achieved within 1 s when applied at its IC50 concentration (10 μM) for IHERG block. Results from “envelope of tails” tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although ∼10% of the available HERG K+ channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block IHERG in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.