Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity
Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity
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DOI：
10.1016/j.drugalcdep.2008.12.009
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发表时间：
2009-05-01
影响因子：
4.2
通讯作者：
Bedynek, Pamela Sheffels
中科院分区：
文献类型：
--
作者：
Kharasch, Evan D.;Walker, Alysa;Bedynek, Pamela Sheffels
背景：奈非那韦可降低美沙酮血浆浓度。美沙酮清除和药物相互作用归因于CYP 3A 4，但美沙酮清除和奈非那韦相互作用的实际机制尚不清楚。我们评估了奈非那韦对美沙酮药代动力学和药效学、肠道和肝脏CYP 3A 4/5活性以及肠道P-糖蛋白转运活性的影响。CYP 3A 4/5和转运体进行了评估，使用阿芬太尼和非索非那定，foreign.Methods：12名健康的HIV阴性志愿者进行了顺序交叉。连续三天，他们接受口服阿芬太尼加非索非那定，静脉注射阿芬太尼，静脉注射加口服美沙酮。奈非那韦治疗后也出现了这种情况。通过质谱法测量血浆和尿液分析物。阿片类药物的作用是通过瞳孔直径的变化（瞳孔缩小）来衡量的。结果：奈非那韦降低静脉和口服美沙酮血浆浓度40- 50%。R-和S-美沙酮的全身清除率、肝脏清除率和肝脏提取率分别增加1.6倍和2倍：表观口服清除率增加1.7倍和1.9倍。奈非那韦立体选择性增加（S > R）美沙酮代谢和代谢产物形成清除率，以及美沙酮肾清除率。美沙酮生物利用度和P-糖蛋白活性的影响最小。奈非那韦使阿芬太尼全身和表观口服清除率分别降低50%和76%。奈非那韦似乎移动美沙酮血浆浓度-效应（缩瞳）curve abnormalized and upward.Conclusions：奈非那韦诱导美沙酮清除增加肾清除率，更是立体选择性增加肝代谢，提取和清除。尽管肝脏CYP 3A 4/5活性抑制50%，首过CYP 3A 4/5活性抑制超过75%，但仍发生诱导，表明CYP 3A在临床美沙酮处置中几乎没有作用。奈非那韦可能改变美沙酮的药效学，增加临床效果。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Background: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively.Methods: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis).Results: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone: apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S > R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward.Conclusions: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects. (C) 2009 Elsevier Ireland Ltd. All rights reserved.