Methadone Pharmacokinetics Are Independent of Cytochrome P4503A (CYP3A) Activity and Gastrointestinal Drug Transport Insights from Methadone Interactions with Ritonavir/Indinavir
Methadone Pharmacokinetics Are Independent of Cytochrome P4503A (CYP3A) Activity and Gastrointestinal Drug Transport Insights from Methadone Interactions with Ritonavir/Indinavir
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DOI：
10.1097/aln.0b013e3181986a9a
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发表时间：
2009-03-01
期刊：
影响因子：
8.8
通讯作者：
Bedynek, Pamela Sheffels
中科院分区：
文献类型：
--
作者：
Kharasch, Evan D.;Hoffer, Christine;Bedynek, Pamela Sheffels
背景：美沙酮清除率是高度可变的，药物相互作用是有问题的。两者都归因于CYP3A，但实际机制尚不清楚。药物相互作用可以提供这样的机制信息。利托那韦/茚地那韦是最早的蛋白酶抑制剂组合之一，可能抑制CYP3A。我们评估了利托那韦/因地那韦对美沙酮药代动力学和药效学的影响，肠道和肝脏CYP3A活性，肠道转运蛋白（p -糖蛋白）活性CYP3A和转运蛋白分别与阿芬太尼和非索非那定进行了评估。方法：12名健康的人类免疫缺陷病毒阴性志愿者进行了连续的三部分交叉试验。连续3天口服阿芬太尼/非索非那定，静脉注射阿芬太尼，静脉注射加口服（氘标记）美沙酮，急性期（3天）和稳态期（2周）利托那韦/茚那韦重复。血浆和尿液分析物采用质谱法测定。阿片类药物的作用通过瞳孔观察来评估。结果：急性和稳态利托那韦/因地那韦对阿芬太尼表观口服清除率的抑制均超过97%，由于肝脏和肠道提取减少，对全身清除率的抑制均超过90%。利托那韦/因地那韦使非索非那定在血浆浓度-时间曲线下的面积增加了4 ~ 5倍，提示对胃肠道p -糖蛋白有明显的抑制作用。利托那韦/因地那韦轻微增加美沙酮n -去甲基化，但对美沙酮血浆浓度、全身或表面口服清除率、肾脏清除率、肝脏提取或清除率或生物利用度没有显著影响。利托那韦/茚地那韦对美沙酮血浆浓度-效应关系无显著影响。结论：抑制肝脏和肠道CYP3A活性是利托那韦/因地那韦药物相互作用的原因。尽管CYP3A活性受到严重抑制，但美沙酮的处置没有变化，这表明CYP3A在临床美沙酮代谢和清除中几乎没有作用。尽管胃肠道p糖蛋白活性受到抑制，但美沙酮的生物利用度没有变化，这表明这种转运蛋白并不限制美沙酮的肠道吸收。
Background: Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively.Methods: Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential three-part crossover. On three consecutive days, they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3 days) and steady state (2 weeks) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis.Results: Alfentanil apparent oral clearance was inhibited more than 97% by both acute and steady state ritonavir/indinavir, and systemic clearance was inhibited more than 90% due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve four- to five-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma con centration-effect relationships.Conclusions: Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.