ADDICTION THERAPY: METABOLISM AND TRANSPORT-MEDIATED DRUG INTERACTIONS

成瘾治疗：代谢和运输介导的药物相互作用

• 批准号: 7883689
• 负责人: Evan D. Kharasch
• 金额: $ 33.86万
• 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/7883689
• 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; 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; substance abuse treatment; 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(申请人提供)：这项研究的总体目标是改善阿片成瘾、艾滋病毒/艾滋病和共存的机会性感染这三种相互交织的疾病的治疗。美沙酮和丁丙诺啡是阿片成瘾的基石疗法，但它们的倾向具有无法解释的变异性。此外，HIV/AIDS的高效抗逆转录病毒疗法(HAART)会导致临床上显著的、复杂的、且对美沙酮和丁丙诺啡的药物相互作用了解不足，这可能导致阿片类药物的戒断、毒性和治疗失败。抗结核药物利福平与美沙酮相互作用，但这种作用是否与丁丙诺啡一起发生，以及两者的潜在机制(S)尚不清楚。需要更好的体外和临床模型来评估人类药物的相互作用。虽然一些丁丙诺啡代谢物在动物中的药理活性已被公认，但它们在人类中的生物活性尚不清楚。HAART药物与成瘾疗法的相互作用既有药代动力学，也有药效学，但还不完全清楚。可预测的治疗指南仍然难以捉摸。这项研究将评估以下假设：丁丙诺啡代谢物在人类中可能具有药理活性，美沙酮、丁丙诺啡和丁丙诺啡代谢物可能是肝脏、肠道和/或血脑转运蛋白的底物，以及HAART和抗结核药物与这些转运体相互作用，改变丁丙诺啡和美沙酮的药代动力学、药效学和临床效果。本研究的目的是定义丁丙诺啡代谢物的人体药理作用，确定以美沙酮、丁丙诺啡和代谢物为底物的人的膜转运体，并评估HAART和利福平对这些途径的影响，以及它们在临床药物相互作用中的作用。将采取协调一致的实验室、翻译和临床方法来实现这些目标。转运蛋白转基因细胞、组织来源细胞和新的共培养细胞模型将用于鉴定与丁丙诺啡和美沙酮相关的转运蛋白、HAART和抗结核病药物的作用。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(S)。临床研究将使用确定阿片类药物脑渗透率和药效学的方法。这些目标的成功完成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：拟议的研究与改进艾滋病毒/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。它还与更好地了解药物如何进入大脑和被身体灭活，以及治疗性药物如何影响健康和患病的个人有关。