Influence of opioid agonists on cardiac human ether-a-go-go related gene K+ currents

We have evaluated the ability of various opioid agonists, including methadone, L-alpha-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 muM 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 muM) 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 similar to10% 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.