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 (I_HERG) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I_HERG, with IC₅₀ values in the 1 to 10 μM range. The other drugs tested were far less potent with respect to I_HERG inhibition. Compared with the reported maximal plasma concentration (C_max) after administration of therapeutic doses of these drugs, the ratio of IC₅₀/C_max 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 I_HERG. In contrast, the lowest ratios of IC₅₀/C_max were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I_HERG was rapid, with steady-state inhibition achieved within 1 s when applied at its IC₅₀ concentration (10 μM) for I_HERG 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 I_HERG 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.