Methadone and HIV drug interactions

这项研究的总体目标是改进美沙酮维持治疗，这是阿片滥用治疗的基石，也是降低艾滋病毒/艾滋病风险的至关重要的有效战略。美沙酮处置的特点是极端、无法解释和不可预测的个体间和个体内变异性，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。细胞色素P3A4的变异性和最重要的是，细胞色素P3A4与药物的相互作用，深刻影响美沙酮的首过代谢和全身清除。美沙酮是新近发现的肠道和中枢神经系统P-糖蛋白(P-gp)的底物，它决定了美沙酮在动物体内的吸收和中枢神经系统的药效学(人类的作用尚不清楚)。HIV/AIDS蛋白水解酶抑制物(HIV-PI)和非核苷类逆转录酶抑制物(NNRTI)是非常有效的细胞色素P3A4调节剂，可引起重大而复杂的(短期和长期效应)药物相互作用，但对药物相互作用知之甚少。HIV-PI在体外是P-gp调节剂，但其临床作用尚不清楚。不幸的轶事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，并产生了不良后果。然而，人们对这种相互作用知之甚少。本研究的总体目标是确定HIV-PI和NNRTI-美沙酮相互作用的机制(S)，并更广泛地验证一种新的体内涉及HIV-PI、NNRTI和美沙酮的药物相互作用的CYP3A4探针，并可推广到其他艾滋病毒/艾滋病药物、药物滥用疗法和CYP3A4药物。其具体目的是：1)验证阿芬太尼(一种体内高度特异的CYP3A4探针)作为快速、非侵入性、廉价的肝脏和肠道CYP3A活性和药物相互作用的替代药物和探针的药效学；2)确定P-gp在美沙酮在人体肠道吸收和CNS药效学中的作用；3)测定HIV-PI(利托那韦、吲地那韦、沙奎那韦、奈非那韦)和NNRTI(奈韦拉平、efavirenz)对肠道P-gp活性、首次通过的CYP3A代谢和肝脏CYP3A活性的影响；4)确定HIV-PI和NNRTI在美沙酮处置和临床效应中的变化机制，可能由P-gp介导的肠道吸收、CyP3A4催化的首过代谢、CyP3A依赖的全身清除和/或P-gp介导的中枢神经系统可及性调节引起；5)建立体内无创的CYP3A活性探针预测美沙酮处置的能力，并快速和非侵入性地检测和预测药物与HIV-PI、NNRTI和美沙酮的相互作用。成功的完成将提供有关美沙酮处置的基本新信息，改善阿片成瘾和艾滋病毒/艾滋病的治疗和结果，并为评估人类最重要的药物代谢酶--细胞色素P3A提供一种新的技术。

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.