In vitro assessment of kratom pharmacokinetic CYP interactions with HIV ART drug metabolism

项目摘要 Kratom在多种药物使用者中很常见，包括艾滋病毒/艾滋病感染者。植物 由于其精神活性和阿片类药物特性而越来越受欢迎。它的使用已成为一个重要的安全 联邦数据库将kratom与多起死亡事件联系起来。Kratom来自Mitragyna的叶子 speciosa在许多州是法律的，广泛可用，并被超过1300万美国消费者使用。这些数据加上 其主要化合物mitragynine的生物活性表明kratom具有药代动力学（PK）潜力 与艾滋病毒抗逆转录病毒疗法（ART）的相互作用，广泛用于PLWHA。药物之间的PK相互作用 如果kratom抑制或诱导I期代谢，则用于HIV ART、毒性和/或缺乏ART疗效结果 酶（特别是细胞色素P450 [CYP]）。关于相互作用的研究有限 kratom和CYP之间的差异，但迄今为止，尚未对任何PK药物的高效kratom剂量进行评估 交互.我们来自奥本大学和俄勒冈州州立大学的多机构团队建议填补这一空白 通过结合我们的专业知识来评估kratom具有PK的假设， 与CYP介导的HIV ART药物的相互作用。临床前研究将在两个特定的领域解决这一假设。 目的：目的1测定植物源性提取物和mitragynine对人肝细胞癌的抑制作用 代谢HIV ART药物的I期CYP。为了确定作用机制，kratom制剂和 抑制特异性CYP的化合物将与广泛使用的第一和第二- 线HIV ART药物方案，并计算表观和总内在清除率。以考虑 从血浆蛋白中置换HIV ART药物（例如，人血清白蛋白），也可以导致kratom- 药物相互作用，快速平衡透析和LC-MS/MS将测量每种kratom生物碱与 人血浆蛋白（来自合并供体）。HIV ART药物的血清蛋白结合也将被 确定比较。目的2：测定红藻提取物和化合物对人肝细胞的诱导作用 代谢HIV ART药物的CYP。为了确定任何PK相互作用的程度，活性提取物或 化合物将与一线和二线HIV ART药物一起重新测试，这些药物是HIV酶的底物， 并计算表观固有清除率。本研究的预期结果是定量评价 kratom和HIV ART底物之间的PK药物相互作用。这些数据应该提供一个基本的 了解HIV ART和kratom之间的PK相互作用以及未来确证性临床研究的依据 试验和方法，以提高kratom用户中艾滋病毒ART的安全性和有效性。最终，洞察力 从这项研究应该改善教育和知识共享之间的病人和临床医生。

PROJECT SUMMARY Kratom use is common among polydrug users, including persons living with HIV/AIDS (PLWHA). The botanical is gaining in popularity due to its psychoactive and opioid properties. Its use has become an important safety issue; and federal databases have linked kratom to multiple deaths. Kratom comes from the leaves of Mitragyna speciosa, is legal in many states, widely available, and used by over 13 million U.S. consumers. These data plus the bioactivity of its major compound, mitragynine, suggest kratom has the potential for pharmacokinetic (PK) interactions with HIV antiretroviral therapies (ART), widely prescribed for PLWHA. PK interactions between drugs used for HIV ART, toxicity, and/or lack of ART efficacy result if kratom inhibits or induces Phase I metabolizing enzymes (particularly the cytochromes P450 [CYPs]). Limited studies demonstrated concerning interactions between kratom and CYPs but, to date, highly potent kratom dosages have not been evaluated for any PK drug interactions. Our multi-institutional team from Auburn University and Oregon State University proposes to fill this knowledge gap by combining our specialized expertise to evaluate the hypothesis that kratom has PK interactions with HIV ART drugs mediated by CYPs. Preclinical studies will address this hypothesis in two specific aims: Aim 1 will assay botanically-authenticated kratom extract and mitragynine for inhibition of human hepatic Phase I CYPs that metabolize HIV ART drugs. To determine a mechanism of action, kratom preparations and compounds that inhibit specific CYPs will be re-assayed in combination with the widely used first- and second- line HIV ART drug regimens, and the apparent and total intrinsic clearances calculated. To account for the displacement of HIV ART drugs from plasma proteins (e.g., human serum albumin) which can also cause kratom- drug interactions, rapid equilibrium dialysis and LC-MS/MS will measure the binding of each kratom alkaloid to human plasma proteins (from pooled donors). The serum protein binding of HIV ART drugs will also be determined for comparison. Aim 2 will assay kratom extract and compounds for induction of human hepatocyte CYPs that metabolize HIV ART drugs. To determine the extent of any PK interactions, active extract or compound will be re-tested with first- and second-line HIV ART drugs that are substrates for the CYP enzyme, and calculate the apparent intrinsic clearance. The anticipated outcome of this study is a quantitative evaluation of PK drug interactions between kratom and HIV ART CYP substrates. These data should provide a fundamental understanding of PK interactions between HIV ART and kratom and a rationale for future confirmatory clinical trials and approaches to improve the safety and efficacy of HIV ART among kratom users. Ultimately, insight from this study should improve education and knowledge-sharing among patients and clinicians.