Current Concepts in Methadone Metabolism and Transport
Current Concepts in Methadone Metabolism and Transport
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DOI：
10.1002/cpdd.326
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发表时间：
2017-03-01
影响因子：
2
通讯作者：
Kharasch, Evan D.
中科院分区：
文献类型：
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作者：
Kharasch, Evan D.
美沙酮是阿片类药物成瘾的基石疗法，也是减少艾滋病毒/艾滋病和丙型肝炎的公共卫生战略。美沙酮也用于急性和慢性疼痛。随着慢性疼痛的使用增加，不良事件也增加了。美沙酮药代动力学和药效学的个体间和个体内的组成性和获得性（药物相互作用）变异性混淆了可靠的临床应用。确定负责美沙酮处置的酶和转运蛋白一直是一个长期追求的理想。最初的体外研究将CYP 3A 4确定为代谢美沙酮。随后，通过外推，CYP 3A 4长期被认为是负责临床美沙酮处置。然而，CYP 2B 6也是美沙酮体外代谢的主要催化剂。现在已经明确确定，CYP 2B 6，而不是CYP 3A 4，是美沙酮代谢、清除、消除和人体血浆浓度的主要决定因素。美沙酮处置易受诱导和抑制药物相互作用的影响。CYP 2B 6遗传也影响美沙酮代谢和清除，在CYP 2B 6 *6携带者中减少，在CYP 2B 6 * 4携带者中增加。CYP 2B 6遗传学可以部分解释美沙酮代谢和清除的个体间差异。因此，由于CYP 2B 6遗传学和CYP 2B 6介导的药物相互作用引起的组成性变异可以改变美沙酮的处置、临床效果和药物安全性。美沙酮不是主要流入或流出转运蛋白的底物。
Methadone is a cornerstone therapy for opioid addiction and a public health strategy for HIV/AIDS and hepatitis C reduction. Methadone is also used for acute and chronic pain. As use for chronic pain has grown, so too have adverse events. Constitutive and acquired (drug interactions) inter-and intraindividual variability in methadone pharmacokinetics and pharmacodynamics confounds reliable clinical use. Identification of enzymes and transporters responsible for methadone disposition has been a long-sought ideal. Initial in vitro studies identified CYP3A4 as metabolizing methadone. Subsequently, by extrapolation, CYP3A4 was long assumed to be responsible for clinical methadone disposition. However, CYP2B6 is also a major catalyst of methadone metabolism in vitro. It has now been unequivocally established that CYP2B6, not CYP3A4, is the principal determinant of methadone metabolism, clearance, elimination, and plasma concentrations in humans. Methadone disposition is susceptible to inductive and inhibitory drug interactions. CYP2B6 genetics also influences methadone metabolism and clearance, which were diminished in CYP2B6*6 carriers and increased in CYP2B6* 4 carriers. CYP2B6 genetics can explain, in part, interindividual variability in methadone metabolism and clearance. Thus, both constitutive variability due to CYP2B6 genetics, and CYP2B6-mediated drug interactions, can alter methadone disposition, clinical effect, and drug safety. Methadone is not a substrate for major influx or efflux transporters.