Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro
Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro
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DOI：
10.1124/dmd.31.6.742
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发表时间：
2003-06-01
影响因子：
3.9
通讯作者：
DeVane, CL
中科院分区：
文献类型：
--
作者：
Wang, JS;DeVane, CL
为了阐明美沙酮（R）-和（S）-对映体的氧化代谢，使用人肝微粒体和重组细胞色素P450酶研究了母体（R）-和（S）-美沙酮的消耗和外消旋2-亚乙基-1，5-二甲基-3，3-二苯基吡咯烷的形成。基于异构体选择性化学抑制剂和表达酶的研究，CYP 3A 4是参与（R）-美沙酮代谢的主要酶。然而，它对（R）-和（S）-美沙酮具有不同的立体选择性。在重组CYP 3A 4中，（R）-美沙酮的代谢清除率约为（S）-美沙酮的4倍。CYP 2C 8也参与美沙酮的代谢，但其对（R）-美沙酮代谢的贡献小于CYP 3A 4。但对于（S）-美沙酮的代谢，CYP 2C 8和CYP 3A 4的作用似乎是相等的。虽然CYP 2D 6参与（R）-和（S）-美沙酮的代谢，但与CYP 3A 4和CYP 2C 8相比，其作用较小。使用临床相关浓度的酮康唑（1 μ M，选择性CYP 3A 4抑制剂）、甲氧苄啶（100 μ M，选择性CYP 2C 8抑制剂）和帕罗西汀（5 μ M，强效CYP 2D 6抑制剂），这些抑制剂分别使（R）-[（S）]美沙酮的肝脏代谢降低69%（47%）、22%（51%）和41%（77%）。然而，帕罗西汀对（R）-和（S）-美沙酮代谢的抑制作用不仅是由于对CYP 2D 6的抑制，还由于对CYP 3A 4的抑制，以及在较小程度上对CYP 2C 8的抑制。目前的体外研究结果表明，CYP 3A 4、CYP 2C 8和CYP 2D 6均参与美沙酮（R）-和（S）-对映体的立体选择性代谢。这些数据表明，联合使用CYP 3A 4和CYP 2C 8抑制剂可能会产生具有临床意义的药物相互作用与美沙酮。
To clarify the oxidative metabolism of methadone (R)- and (S)-enantiomers, the depletion of parent (R)- and (S)-methadone and the formation of racemic 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine were studied using human liver microsomes and recombinant cytochrome P450 enzymes. Based on studies with isoform-selective chemical inhibitors and expressed enzymes, CYP3A4 was the predominant enzyme involved in the metabolism of (R)-methadone. However, it has different stereoselectivity toward (R)- and (S)-methadone. In recombinant CYP3A4, the metabolic clearance of (R)-methadone was about 4-fold higher than that of (S)-methadone. CYP2C8 is also involved in the metabolism of methadone, but its contribution to the metabolism of (R)-methadone was smaller than that of CYP3A4. But for the metabolism of (S)-methadone, the roles of CYP2C8 and CYP3A4 appeared equal. Although CYP2D6 is involved in the metabolism of (R)- and (S)-methadone, its role was smaller compared with CYP3A4 and CYP2C8. Using clinically relevant concentrations of ketoconazole (1 muM, selective CYP3A4 inhibitor), trimethoprim (100 muM, selective CYP2C8 inhibitor), and paroxetine (5 muM, potent CYP2D6 inhibitor), these inhibitors decreased the hepatic metabolism of (R)-[(S)] methadone by 69% (47%), 22% (51%), and 41% (77%), respectively. However, inhibition of the metabolism of (R)- and (S)-methadone by paroxetine was due to inhibition not only of CYP2D6, but also CYP3A4 and, to a minor extent, CYP2C8. The present in vitro findings indicated that CYP3A4, CYP2C8, and CYP2D6 are all involved in the stereoselective metabolism of methadone (R)- and (S)-enantiomers. These data suggest that coadministration of inhibitors of CYP3A4 and CYP2C8 may produce clinically significant drug-drug interactions with methadone.