The Function of Methadone in Metabolic-& Pharmacokinetic-Based Drug Interactions

描述(由申请人提供)：到目前为止，美沙酮-药物相互作用是一个在已发表的科学文献中具有不对称特征的研究领域。大多数报告集中于其他药物如何影响美沙酮(MD)的代谢和药代动力学特征的表征。然而，很少有人对MD调节其他药物的代谢和药代动力学(MPK)的可能性进行调查，这可能导致严重的药物-药物相互作用(DDIS)。此外，几乎没有机械性的证据被探索过。这项工作的目的是阐明MD如何扰乱共同使用或共同滥用药物的代谢和药代动力学命运，从而从历史上被忽视的角度进行研究。这种研究方法是新颖的，有可能产生巨大的影响，因为它从一个相对较新的研究角度审查了一种更古老但非常具有临床必要性的药物疗法。这个项目的比例是，考虑到MD患者和滥用者人口的不断增长，越来越多的使用者越来越容易受到DDIS的不良影响。因此，确定MD可能产生的影响&确定可能的责任机制变得越来越重要。我们假设MD可以干扰关键的I、II和III期药物代谢酶(DME)和转运体；核受体可能参与介导这种干扰；MD的干扰可以改变其他药物的MPK。因此，本项目的具体目标是研究MD如何影响关键DME的表达，研究核受体CAR和PXR所起的机制作用，并探索由此产生的以MPK为基础的DDIS。这些MD-药物相互作用有望在临床上具有重要意义，因此，将使用一种混合了体外代谢研究、体外PK研究和在体啮齿动物PK研究的翻译方法；将使用诸如人类肝细胞培养、基于细胞的报告分析、实时聚合酶链式反应、高效液相色谱和共聚焦显微镜等实验技术。美沙酮是治疗海洛因依赖最可靠的替代品，也是治疗慢性疼痛的处方药。这项研究对整个公共卫生行业非常重要，特别是对临床医生和将MD作为美沙酮维持疗法一部分进行管理的研究人员。

DESCRIPTION (provided by applicant): To date, methadone-drug interactions is a field of research that is characterized asymmetrically among published scientific literature. The majority of reports focus intensively on characterization of how other drugs affect the metabolic & pharmacokinetic profile of methadone (MD). Little inquiry, however, has been made into the potential for MD to modulate the metabolism & pharmacokinetics (MPK) of other drugs, which can cause severe drug-drug interactions (DDIs). Moreover, little to no mechanistic evidence has been explored. The purpose of this work is to elucidate how MD disrupts the metabolic & pharmacokinetic fate of commonly co-administered or co-abused drugs, thereby undertaking research from a perspective that has been historically overlooked. This approach to research is novel, and has the potential for huge impact, because it examines an older, but very clinically essential drug therapy, from a relatively new research angle. The ration- ale for this project is that, given the growing population of MD patients & abusers, a growing subset of users are progressively susceptible to experiencing adverse effects from DDIs. Thus, it has become increasingly important to establish the effects that MD can have & to identify the mechanisms that may be responsible. We hypothesize that MD can perturb key phase I, II & III drug-metabolizing enzymes (DMEs) & transporters; that nuclear receptors may be involved in mediating this disturbance; and that MD perturbation can alter the MPK of other drugs. Thus, the specific aims of this project are to examine how MD influences the express- ion of key DMEs such as CYP2B6, to investigate the mechanistic roles played by nuclear receptors CAR & PXR, and to explore the resultant MPK-based DDIs. These MD-drug interactions are expected to be clinic- ally significant, and as such, a translational approach involving a mixture of in vitro metabolism studies, in vitro PK studies, & in vivo rodent PK studies, will be used; experimental techniques such as human hepatocyte cultures, cell-based reporter assays, realtime polymerase chain reaction, HPLC,& confocal microscopy will be employed. Methadone is the most established substitute for treating heroin dependence & is also prescribed to treat chronic pain. This research is of great importance to the overall public health industry, particularly to clinicians & researchers that administer MD as part of methadone maintenance therapy.