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

卡痛叶药代动力学 CYP 与 HIV ART 药物代谢相互作用的体外评估

• 批准号: 10746628
• 负责人: Angela Isabel Calderon
• 金额: $ 8.82万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746628
• 关键词: Acceleration; Adverse event; Affect; Alcohol abuse; Alkaloids; Analytical Chemistry; Applications Grants; Area; Binding; Binding Proteins; Biological Assay; Blood; Botanicals; CYP2D6 gene; CYP3A4 gene; Cells; Cessation of life; Clinical; Clinical Research; Core Facility; Cytochrome P450; Data; Databases; Dialysis procedure; Dose; Drug Interactions; Drug Kinetics; Drug usage; Education; Ensure; Enzymes; Equilibrium; Foundations; Funding; Future; Glucuronosyltransferase; Goals; HIV; HIV antiretroviral; HIV/AIDS; HepG2; Hepatic; Hepatocyte; Human; In Vitro; Incubated; Individual; Institution; Investigation; Knowledge; Leadership; Legal; Link; Liver Microsomes; Measures; Mediating; Metabolism; Mitragyna; National Institute of Drug Abuse; Natural Products; Natural Substance; Opioid; Oregon; Outcome Study; Patients; Persons; Pharmaceutical Preparations; Pharmacognosy; Pharmacology; Pharmacy facility; Phase; Physiological; Plant Leaves; Plasma; Plasma Proteins; Positioning Attribute; Preparation; Property; Quantitative Evaluations; Recombinants; Recommendation; Regimen; Reporting; Research; Rifampin; Risk; Safety; Serotonin Syndrome; Serum; Serum Albumin; Serum Proteins; Standardization; Stimulant; Stress; Substance abuse problem; System; Tenofovir; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Protocols; Treatment-related toxicity; United States Food and Drug Administration; United States National Institutes of Health; Universities; alcohol risk; antiretroviral therapy; clinically relevant; confirmatory clinical trial; dosage; drug metabolism; emtricitabine; follow-up; improved; in vitro Model; innovation; insight; instrumentation; mRNA Expression; negative affect; pharmacokinetic model; preclinical study; quetiapine; substance use; therapy outcome; venlafaxine

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.

项目总结 KrATOM的使用在包括艾滋病毒/艾滋病患者(PLWHA)在内的多药物使用者中很常见。植物学 由于其具有精神活性和阿片类药物的特性，它越来越受欢迎。使用它已成为一种重要的安全措施 联邦数据库将Krtom与多起死亡联系起来。KrATOM来自密特拉格纳的叶子 在许多州是合法的，广泛使用，并被1300多万美国消费者使用。这些数据加上 其主要化合物米曲吉宁的生物活性表明，KrATOM具有潜在的药代动力学(PK)。 与艾滋病毒抗逆转录病毒疗法(ART)的相互作用，该疗法被广泛用于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疗效的结果 酶(特别是细胞色素P450[Cyps])。关于相互作用的有限研究表明 KrATOM和CyPS之间的差异，但到目前为止，还没有对任何PK药物评估高效力KrATOM剂量 互动。我们来自奥本大学和俄勒冈州立大学的多机构团队提议填补这一空缺 通过结合我们的专业知识来评估Krtom有PK的假设 Cyps介导的HIV抗逆转录病毒药物的相互作用。临床前研究将在两个具体的方面解决这一假设 目的：Aim 1将检测经植物学鉴定的Krtom提取物和米托吗宁对人肝脏的抑制作用 代谢HIV抗逆转录病毒药物的第一阶段细胞色素P450。为了确定作用机制，KrATOM制剂和 抑制特定细胞色素P450的化合物将与广泛使用的第一和第二- 列出HIV抗逆转录病毒药物方案，并计算表观和总的内在清除。来解释一下 艾滋病毒抗逆转录病毒药物从血浆蛋白(例如人血清白蛋白)中取代，这也会导致Krtom- 药物相互作用、快速平衡透析和LC-MS/MS将测量每个Krtom生物碱与 人血浆蛋白(来自集合供体)。HIV抗逆转录病毒药物的血清蛋白结合也将是 确定进行比较。目的2检测KrATOM提取物及其化合物对人肝细胞的诱导作用 代谢HIV抗逆转录病毒药物的细胞周期蛋白。为了确定任何PK交互的程度，活性提取物或 化合物将用作为CYP酶底物的一线和二线HIV抗逆转录病毒药物进行重新测试， 并计算表观固有间隙。这项研究的预期结果是定量评估。 KrATOM和HIV ART CYP底物之间PK药物相互作用的研究。这些数据应该提供一个基本的 理解HIV ART和KrATOM之间的PK相互作用和未来验证性临床的理论基础 在KrATOM使用者中提高艾滋病毒抗逆转录病毒疗法安全性和有效性的试验和方法。归根结底，洞察 这项研究将改善患者和临床医生之间的教育和知识共享。