ADDICTION THERAPY: METABOLISM AND TRANSPORT-MEDIATED DRUG INTERACTIONS

成瘾治疗：代谢和转运介导的药物相互作用

• 批准号: 7681770
• 负责人: Evan D. Kharasch
• 金额: $ 34.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681770
• 关键词: AIDS/HIV problem; Absence of pain sensation; Acute; Affect; Animals; Antitubercular Agents; Biological; Biological Availability; Blood; Blood - brain barrier anatomy; Brain; Buprenorphine; CYP3A4 gene; Carrier Proteins; Cell model; Cell surface; Cells; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Pharmacology; Clinical Protocols; Clinical Research; Clinical Treatment; Coculture Techniques; Communicable Diseases; Complex; Crime; Cultured Cells; Cytochromes; Disease; Dose; Drug Interactions; Drug Kinetics; Drug abuse; Drug usage; Enterocytes; Epidemic; Event; Glucuronides; Goals; Guidelines; HIV; HIV therapy; Hepatic; Hepatocyte; Highly Active Antiretroviral Therapy; Human; In Vitro; Incidence; Individual; Intestines; Kinetics; Knowledge; Laboratories; Laboratory Study; Liver; Mediating; Membrane Transport Proteins; Metabolism; Methadone; Methods; Modeling; Modern Medicine; Opiate Addiction; Opiates; Opioid; Opportunistic Infections; Oral; Pathway interactions; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Plasma; Play; Productivity; Public Health; Replacement Therapy; Research; Resistance; Rifampin; Role; Safety; Study models; Substance abuse problem; Swelling; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Failure; Treatment outcome; Tuberculosis; Ventilatory Depression; Withdrawal; Xenobiotics; absorption; addiction; base; clinical effect; clinically significant; cost; improved; in vivo; novel; opioid abuse; patient population; prevent; programs; public health relevance; response; social; success; tuberculosis drugs; tuberculosis treatment

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.

描述（由申请人提供）：本研究的总体目标是改善阿片成瘾、艾滋病毒/艾滋病和共存机会性感染等相互交织的疾病的治疗。美沙酮和丁丙诺啡是阿片类药物成瘾的基石疗法，但它们的倾向具有无法解释的变异性。此外，针对艾滋病毒/艾滋病的高效抗逆转录病毒疗法（HAART）会导致与美沙酮和丁丙诺啡的临床显着、复杂且尚不充分了解的药物相互作用，这可能导致阿片类药物戒断、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相互作用，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具有药理活性，但它们在人体中的生物活性尚不清楚。 HAART 药物与成瘾疗法的相互作用是药代动力学和药效学的，但尚不完全清楚。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对人体具有药理活性，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，以及 HAART 和抗结核药物与这些转运蛋白相互作用改变丁丙诺啡和美沙酮的药代动力学、药效学和临床效果。该研究计划的目的是定义丁丙诺啡代谢物的人体药理学，识别以美沙酮、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中的作用互动。将采取协调一致的实验室、转化和临床方法来实现这些目标。转运蛋白转染细胞、组织来源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 和抗结核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中，以识别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。成功实现这些目标将提供有关丁丙诺啡处置的基本新信息，改善治疗指导和安全性，并加强阿片成瘾和艾滋病毒/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、药物相互作用以及药物相互作用引起的严重不良并发症发生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患病个体。