Methadone and HIV drug interactions

本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/艾滋病风险的重要有效策略。美沙酮处置的特点是极端的，无法解释的和不可预测的个体间和个体内变异性，导致阿片戒断，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的变异性，最重要的是，CYP3A4的药物相互作用，深刻地影响美沙酮的首过代谢和全身清除。美沙酮是一种新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（对人类的作用尚不清楚）。HIV/AIDS蛋白酶抑制剂（HIV- pi）和非核苷逆转录酶抑制剂（NNRTI）是非常有效的CYP3A4调节剂，引起显著和复杂的（短期和长期的影响），但对药物相互作用知之甚少。HIV-PI是P-gp体外调节剂，但其临床效果尚不清楚。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，并伴有不良后果。然而，人们对这种相互作用知之甚少。研究的总体目标是确定HIV- pi和NNRTI-美沙酮相互作用的机制，并更广泛地验证一种新的体内CYP3A4探针，用于检测涉及HIV- pi、NNRTI和美沙酮的药物相互作用，并推广到其他HIV/AIDS药物、药物滥用治疗和CYP3A4药物。具体目的是：1)验证阿芬太尼（一种高度特异性的体内CYP3A4探针）作为一种快速、无创、廉价的药代动力学替代品和肝脏和肠道CYP3A活性和药物相互作用的探针的药效学；2)确定P-gp在人体美沙酮肠道吸收和中枢神经系统药效学中的作用；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、依非韦伦）对肠道P-gp活性、首过CYP3A代谢和肝脏CYP3A活性的影响；4)确定HIV-PI和NNRTI对美沙酮处置和临床效果的改变机制，可能是由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的调节引起的；5)建立无创体内CYP3A活性探针预测美沙酮处置的能力，以及快速、无创地检测和预测与HIV-PI、NNRTI和美沙酮的药物相互作用。成功的完成将为美沙酮处置提供新的基础信息，改善阿片类药物成瘾和HIV/AIDS的治疗和结果，并为评估人类最重要的药物代谢酶CYP3A提供新的技术。

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.