ADDICTION THERAPY: METABOLISM AND TRANSPORT-MEDIATED DRUG INTERACTIONS

描述（由申请人提供）：本研究的总体目标是改善阿片类药物成瘾，艾滋病毒/艾滋病和共存的机会性感染交织疾病的治疗。美沙酮和丁丙诺啡是阿片类药物成瘾的基础疗法，但它们的倾向性具有无法解释的变异性。此外，用于HIV/AIDS的高效抗逆转录病毒疗法（HAART）引起与美沙酮和丁丙诺啡的临床显著的、复杂的和不充分理解的药物相互作用，这可能导致阿片类戒断、毒性和治疗失败。抗结核药物利福平与美沙酮相互作用，但丁丙诺啡是否会发生这种作用，以及两者的潜在机制尚不清楚。需要更好的体外和临床模型来评估人类药物相互作用。虽然一些丁丙诺啡代谢物在动物中的药理学活性是公认的，但其在人体中的生物学活性尚不清楚。HAART药物与成瘾治疗的相互作用是药代动力学和药效学，但不完全了解。可预测的治疗指南仍然难以捉摸。本研究将评估以下假设：丁丙诺啡代谢物可能在人体内具有抗抑郁活性;美沙酮、丁丙诺啡和丁丙诺啡代谢物可能是肝、肠和/或血脑转运蛋白的底物; HAART和抗结核药物与这些转运蛋白相互作用，从而改变丁丙诺啡和美沙酮的药代动力学、药效学和临床效应。本研究计划的目的是确定丁丙诺啡代谢物的人体药理学，确定美沙酮、丁丙诺啡和代谢物为底物的人膜转运蛋白，并评估HAART和利福平对这些途径的影响及其在临床药物相互作用中的作用。一个协调一致的实验室，翻译和临床方法，这些目标将被追求。转运蛋白转染的细胞、组织来源的细胞和新型共培养细胞模型将用于鉴定与丁丙诺啡和美沙酮、HAART和抗TB药物的作用相关的转运蛋白。新型体内探针将用于机械驱动和治疗适用的临床方案，以确定药物相互作用及其机制。临床研究将使用确定阿片类药物脑渗透和药效学的方法。这些目标的成功实现将提供关于丁丙诺啡处置的基本新信息，改进治疗指导和安全性，并加强阿片类药物成瘾和艾滋病毒/艾滋病的治疗和结果。 公共卫生相关性：拟议的研究与改善艾滋病毒/艾滋病、药物滥用、药物相互作用和药物相互作用引起的严重不良并发症发病率上升等重大公共卫生问题的临床治疗有关。它还有助于更好地了解药物如何进入大脑并被身体灭活，以及治疗药物如何影响健康和生病的个体。

DESCRIPTION (provided by applicant): The overall goal of this research is to improve treatment of the intertwined diseases of opiate addiction, HIV/AIDS and coexisting opportunistic infections. Methadone and buprenorphine are the cornerstone therapies for opiate addiction, however their disposition is characterized by unexplained variability. Moreover, highly active antiretroviral therapy (HAART) for HIV/AIDS causes clinically significant, complex, and insufficiently understood drug interactions with both methadone and buprenorphine, which may cause opiate withdrawal, toxicity, and treatment failures. The antitubercular drug rifampin interacts with methadone, but whether this occurs with buprenorphine, and the underlying mechanism(s) for either, are unknown. Better in vitro and clinical models for assessing human drug interactions are needed. While pharmacologic activity in animals is recognized for some buprenorphine metabolites,their biological activity in humans is unknown. HAART drug interactions with addiction therapies are both pharmacokinetic and pharmacodynamic, but incompletely understood. Predictable therapeutic guidelines remain elusive. This research will evaluate the hypotheses that buprenorphine metabolites may be pharmacologically active in humans, that methadone, buprenorphine, and buprenorphine metabolites may be substrates for hepatic, intestinal, and/or blood brain transport proteins, and that HAART and antitubercular drugs interact with these transporters to alter buprenorphine and methadone pharmacokinetics, pharmacodynamic, and clinical effects. The aims of this research program are to define the human pharmacology of buprenorphine metabolites, identify the human membrane transporters for which methadone, buprenorphine, and metabolites are substrates, and assess the influence of HAART and rifampin on these pathways, and their role in clinical drug interactions. A concerted laboratory, translational and clinical approach to these aims will be pursued. Transporter-transfected cells, tissue-derived cells, and novel co-culture cell models will be used to identify transporters relevant to buprenorphine and methadone, the effects of HAART and anti-TB drugs. Novel in vivo probes will be used in mechanistically-driven and therapeutically applicable clinical protocols to identify drug interactions and their mechanism(s). Clinical studies will use methods for determining opioid brain penetration and pharmacodynamics. Successful completion of the aims will provide fundamental new information on buprenorphine disposition, improve therapeutic guidance and safety, and enhance the treatments and outcomes of opiate addiction and HIV/AIDS. Public Health Relevance: The proposed research is relevant to improving the clinical treatment of the significant public health problems of HIV/AIDS, substance abuse,drug interactions,and the rising incidence of serious adverse complications from drug interactions. It is also relevant to creating a better basic understanding of how drugs enter the brain and are inactivated by the body, and how therapeutic drugs affect healthy and ill individuals.