Methadone and HIV drug interactions

这项研究的总体目标是改善美沙酮维持治疗，这是阿片类药物滥用治疗的基石，也是降低艾滋病毒/艾滋病风险的一项极其有效的战略。 美沙酮倾向的特点是极端的，无法解释的和不可预测的个体间和个体内的变异性，导致阿片类药物戒断，副作用和治疗失败。 美沙酮肠道首过代谢和全身清除主要由细胞色素P4503A4催化。 CYP3A4变异性，最重要的是，CYP3A4药物相互作用，深刻影响美沙酮首过代谢和全身清除率。 美沙酮是一种新认识到的肠道和中枢神经系统P-糖蛋白（P-gp）的底物，决定了美沙酮在动物中的吸收和中枢神经系统药效学（人类作用未知）。 HIV/AIDS蛋白酶抑制剂（HIV-PI）和非核苷类逆转录酶抑制剂（NNRTI）是非常有效的CYP3A4调节剂，可引起显著和复杂的（短期与长期效应），但对药物相互作用了解甚少。 HIV-PI是P-gp的体外调节剂，但其临床作用尚不清楚。不幸的是，目前检测美沙酮药物相互作用的方法，最近发现了具有临床意义的HIV-PI和NNRTI-美沙酮相互作用，具有不良后果。 然而，人们对这种相互作用知之甚少。 总体研究目标是确定HIV-PI和NNRTI-美沙酮相互作用的机制，更广泛地验证一种新型体内CYP3A4探针，用于涉及HIV-PI、NNRTI和美沙酮的药物相互作用，并可推广至其他HIV/AIDS药物、药物滥用治疗和CYP3A4药物。 具体目标是：1）验证阿芬太尼的药效学（高度特异性的体内CYP3A4探针）作为肝和肠CYP3A活性和药物相互作用的快速、非侵入性、廉价的药代动力学替代物和探针; 2）确定P-gp在美沙酮肠吸收和人CNS药效学中的作用; 3）测定HIV-PI（利托那韦、茚地那韦、沙奎那韦、奈非那韦）和NNRTI（奈韦拉平、依法韦仑）对肠道P-gp活性、首过CYP3A代谢和肝脏CYP3A活性的影响; 4）鉴定HIV-PI和NNRTI改变美沙酮处置和临床效果的机制，其可能由P-gp介导的肠道吸收、CYP3A4催化的首过代谢、CYP3A依赖性全身清除和/或P-gp介导的CNS可及性的调节引起; 5）建立CYP3A活性的非侵入性体内探针预测美沙酮处置的能力，以及快速和非侵入性地检测和预测与HIV-PI、NNRTI和美沙酮的药物相互作用的能力。 成功完成将提供美沙酮处置的基本新信息，改善阿片类药物成瘾和艾滋病毒/艾滋病的治疗和结果，并提供一种新的技术来评估CYP3A，人类最重要的药物代谢酶。

The overall goal of this research is to improve methadone maintenance treatment, the cornerstone of opiate abuse therapy and a vitally effective strategy for HIV/AIDS risk reduction. Methadone disposition is characterized by extreme, unexplained and unpredictable inter- and intra- individual variability, causing opiate withdrawal, side effects, and treatment failures. Methadone intestinal first-pass metabolism and systemic clearance are catalyzed predominantly by cytochrome P4503A4. CYP3A4 variability and most importantly, CYP3A4 drug interactions, profoundly affect methadone first-pass metabolism and systemic clearance. Methadone is a newly recognized substrate for intestinal and CNS P-glycoprotein (P-gp), which determines methadone absorption and CNS pharmacodynamics in animals (a human role is unknown). The HIV/AIDS protease inhibitors (HIV-PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) are exquisitely potent CYP3A4 modulators, causing significant and complex (short- vs long-duration effects) yet poorly understood drug interactions. HIV-PI are P-gp modulators in vitro, yet their clinical effects are unknown. Unfortunate anecdote, the current way of detecting methadone drug interactions, has recently identified clinically significant HIV-PI and NNRTI-methadone interactions, with adverse outcomes. Nevertheless, such interactions are poorly understood. The overall research objective is to identify the mechanism(s) of HIV-PI and NNRTI-methadone interactions, and more generally validate a novel in vivo CYP3A4 probe for drug interactions involving HIV-PI, NNRTI, and methadone, and generalizable to other HIV/AIDS drugs, drug abuse therapies, and CYP3A4 drugs. The specific aims are to: 1) validate the pharmacodynamics of alfentanil (a highly specific in vivo CYP3A4 probe) as a rapid, noninvasive, inexpensive pharmacokinetic surrogate and probe for hepatic and intestinal CYP3A activity and drug interactions;2) determine the role of P-gp in methadone intestinal absorption and CNS pharmacodynamics in humans;3) determine HIV-PI (ritonavir, indinavir, saquinavir, nelfinavir)and NNRTI (nevirapine, efavirenz) effects on intestinal P-gp activity, first-pass CYP3A metabolism, and hepatic CYP3A activity;4) identify mechanisms of HIV-PI and NNRTI alterations in methadone disposition and clinical effect, potentially caused by modulation of P-gp-mediated intestinal absorption, CYP3A4-catalyzed first-pass metabolism, CYP3A-dependent systemic clearance, and/or P-gp- mediated CNS accessibility;5) establish the ability of noninvasive in vivo probe of CYP3A activity to predict methadone disposition, and to rapidly and noninvasively detect and predict drug interactions with HIV-PI, NNRTI, and methadone. Successful completion will provide fundamental new information on methadone disposition, improve the treatments and outcomes of opiate addiction and HIV/AIDS, and provide a novel technology for assessing CYP3A, the most important drug metabolism enzyme in humans.