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Vol. 303, Issue 2, 688-694, November 2002
Department of Pharmacology, Georgetown University Medical Center,
Washington, DC (A.N.K., K.A.M., M.J.K., and S.N.E.); Department of
Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York
(C.A.K., P.L.M.); and Department of Medicine, University of Arizona
Health Sciences Center, Tucson, Arizona (R.L.W.)
We have evaluated the ability of various opioid agonists, including
methadone, L-
-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.
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