Katchman Alexander N, McGroary Kelly A, Kilborn Michael J, Kornick Craig A, Manfredi Paolo L, Woosley Raymond L, Ebert Steven N
Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20007, USA.
J Pharmacol Exp Ther. 2002 Nov;303(2):688-94. doi: 10.1124/jpet.102.038240.
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 IC(50) values in the 1 to 10 microM 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 IC(50)/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 IC(50)/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 IC(50) concentration (10 microM) 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 approximately 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.
我们评估了多种阿片类激动剂，包括美沙酮、左旋 - α - 乙酰美沙朵（LAAM）、芬太尼、哌替啶、可待因、吗啡和丁丙诺啡，在稳定转染了人类醚 - 去极化相关基因（HERG）钾通道基因的人类细胞中阻断心脏HERG钾电流（I(HERG)）的能力。我们的结果表明，LAAM、美沙酮、芬太尼和丁丙诺啡是I(HERG)的有效抑制剂，IC(50)值在1至10微摩尔范围内。所测试的其他药物对I(HERG)的抑制作用要弱得多。与这些药物治疗剂量给药后报告的最大血浆浓度（C(max)）相比，可待因和吗啡的IC(50)/C(max)比值最高（分别>455和>400），因此表明这些药物在阻断I(HERG)方面具有（所测试化合物中）最宽的安全范围。相比之下，LAAM和美沙酮的IC(50)/C(max)比值最低（分别为2.2和2.7）。进一步研究表明，美沙酮对I(HERG)的阻断作用迅速，当以其I(HERG)阻断的IC(50)浓度（10微摩尔）应用时，1秒内即可达到稳态抑制。“尾电流包络”测试结果表明，尽管约10%的可用HERG钾通道显然在关闭状态下被阻断，但大多数阻断发生在通道处于开放和/或失活状态时。LAAM也得到了类似的结果。这些结果表明，LAAM和美沙酮可在临床相关浓度下阻断转染细胞中的I(HERG)，从而为一些接受LAAM或美沙酮治疗的患者中观察到的不良心脏效应提供了一种合理的机制。
