尽管抑制了肝和肠道细胞色素 P4503A（CYP3A），但缺乏茚地那韦对美沙酮处置的影响。
Lack of indinavir effects on methadone disposition despite inhibition of hepatic and intestinal cytochrome P4503A (CYP3A).
机构信息
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri 63110-1093, USA.
出版信息
Anesthesiology. 2012 Feb;116(2):432-47. doi: 10.1097/ALN.0b013e3182423478.
BACKGROUND
Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine).
METHODS
Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis.
RESULTS
Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir.
CONCLUSIONS
Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability.
背景
美沙酮的处置和药效动力学高度易受与抗逆转录病毒药物相互作用的影响。美沙酮清除率和药物相互作用归因于细胞色素 P4503A4（CYP3A4），但实际机制尚不清楚。药物相互作用在临床上和机制上都具有信息性。本研究评估了蛋白酶抑制剂茚地那韦对美沙酮药代动力学和药效学、肝和肠 CYP3A4/5 活性（使用阿芬太尼）和肠转运体活性（使用非索非那定）的影响。
方法
12 名健康志愿者进行了连续交叉试验。在连续三天，他们接受了口服阿芬太尼加非索非那定、静脉内阿芬太尼和静脉内加口服（氘标记）美沙酮。在 2 周的茚地那韦后重复了这一过程。通过质谱法测量血浆和尿液分析物。通过瞳孔缩小测量阿片类药物的作用。
结果
茚地那韦显著抑制了肝和首过 CYP3A 活性。静脉内阿芬太尼全身清除率和肝提取率降低至对照的 40-50%，口服表观清除率降低至对照的 30%，肠提取率降低一半，表明肝和首过 CYP3A 活性抑制 50%和 70%。茚地那韦使非索非那定的血浆浓度-时间曲线下面积增加了 3 倍，表明 P-糖蛋白抑制作用显著。茚地那韦对美沙酮的血浆浓度、美沙酮 N-去甲基化、全身或口服表观清除率、肾清除率、肝提取率或清除率或生物利用度均无显著影响。美沙酮的血浆浓度-效应关系不受茚地那韦的影响。
结论
尽管对肝和肠 CYP3A 活性有显著抑制作用，但茚地那韦对美沙酮的 N-去甲基化和清除率没有影响，这表明 CYP3A 在单剂量美沙酮的临床处置中作用很小或没有作用。胃肠道转运体活性的抑制对美沙酮的生物利用度没有影响。
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