Eap C B, Crettol S, Rougier J-S, Schläpfer J, Sintra Grilo L, Déglon J-J, Besson J, Croquette-Krokar M, Carrupt P-A, Abriel H
Unit of Biochemistry and Clinical Psychopharmacology, Centre for Psychiatric Neurosciences, University Department of Psychiatry-CHUV, Hospital of Cery, Prilly-Lausanne, Switzerland.
Clin Pharmacol Ther. 2007 May;81(5):719-28. doi: 10.1038/sj.clpt.6100120. Epub 2007 Feb 28.
Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.
美沙酮可抑制心脏钾通道hERG，并可导致QT间期延长。美沙酮具有手性，但其治疗活性主要归因于（R）-美沙酮。使用表达hERG的细胞进行的全细胞膜片钳实验表明，（S）-美沙酮阻断hERG电流的效力比（R）-美沙酮强3.5倍（37℃时的半数最大抑制浓度（IC50）：2和7微摩尔）。由于细胞色素P450 2B6慢代谢者（SM）状态导致代谢（S）-美沙酮的能力降低，因此对179例接受（R，S）-美沙酮治疗的患者进行了心电图、细胞色素P450 2B6基因型以及（R）-和（S）-美沙酮血浆浓度检测。细胞色素P450 2B6 SMs（*6/6基因型；439±25毫秒；n = 11）的平均心率校正QT（QTc）高于广泛代谢者（非6/*6；421±25毫秒；n = 168；P = 0.017）。细胞色素P450 2B6 SM状态与QTc延长风险增加相关（比值比=4.5，95%置信区间=1.2 - 17.7；P = 0.03）。本研究报告了首个与美沙酮代谢相关的遗传因素，该因素可能增加心律失常和猝死风险。给予（R）-美沙酮可降低这种风险。
