Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers
Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers
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DOI：
10.1038/sj.clpt.6100120
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发表时间：
2007-05-01
影响因子：
6.7
通讯作者：
Abriel, H.
中科院分区：
文献类型：
--
作者：
Eap, C. B.;Crettol, S.;Abriel, H.
美沙酮抑制心脏钾通道hERG，可导致QT间期延长。美沙酮是手性的，但其治疗活性主要是由于(R)-美沙酮。利用表达hERG的细胞进行的全细胞膜片钳实验表明，(S)-美沙酮对hERG电流的阻断作用是(R)-美沙酮的3.5倍(IC（50) S（半最大抑制浓度），37℃：2和7 μ M）。由于CYP2B6慢代谢（SM）状态导致代谢(S)-美沙酮的能力降低，我们获得了179例接受（R， S）-美沙酮治疗的患者的心电图、CYP2B6基因型以及(R)-和(S)-美沙酮的血浆浓度。CYP2B6组（*6/*6基因型；439725 ms; n = 11）的平均心率校正QT （QTc）高于广泛代谢组（非*6/*6；421725 ms; n = 168; P = 0.017）。CYP2B6 SM状态与QTc延长的风险增加相关（优势比为4.5,95%可信区间为1.2-17.7;P = 0.03）。这项研究报告了第一个与美沙酮代谢有关的遗传因素，可能会增加心律失常和猝死的风险。这种风险可以通过使用(R)-美沙酮来降低。
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 ( IC(50)s ( half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 mu M). 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; 439725 ms; n = 11) than in extensive metabolizers ( non *6/*6; 421725 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.