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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要卡痛在多种药物使用者中很常见，包括艾滋病毒/艾滋病患者 (PLWHA)。植物学的由于其精神活性和阿片类药物的特性而越来越受欢迎。它的使用已成为一个重要的安全问题问题;联邦数据库已将卡痛叶与多起死亡事件联系起来。卡痛来自帽柱木的叶子 spiosa 在许多州都是合法的，广泛使用，有超过 1300 万美国消费者使用。这些数据加上其主要化合物帽柱木碱的生物活性表明卡痛叶具有药代动力学 (PK) 潜力与广泛用于 PLWHA 的 HIV 抗逆转录病毒疗法 (ART) 的相互作用。药物之间的PK相互作用如果卡痛叶抑制或诱导 I 期代谢，则用于 HIV ART、毒性和/或缺乏 ART 功效酶（特别是细胞色素 P450 [CYP]）。有限的研究表明有关相互作用卡痛叶和 CYP 之间存在差异，但迄今为止，尚未对任何 PK 药物的高效卡痛叶剂量进行评估互动。我们来自奥本大学和俄勒冈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卡痛叶具有 PK 的假设，从而实现知识差距 CYP 介导的与 HIV ART 药物的相互作用。临床前研究将在两个具体方面解决这一假设目标：目标 1 将测定植物学验证的卡痛叶提取物和帽柱木碱对人类肝脏的抑制作用代谢 HIV ART 药物的 I 期 CYP。为了确定作用机制，卡痛叶制剂和抑制特定 CYP 的化合物将与广泛使用的第一和第二化合物结合重新测定。线 HIV ART 药物治疗方案，并计算表观清除率和总内在清除率。考虑到 HIV ART 药物从血浆蛋白（例如人血清白蛋白）中置换出来，这也可能导致 kratom- 药物相互作用、快速平衡透析和 LC-MS/MS 将测量每种卡痛生物碱与人类血浆蛋白（来自汇集的供体）。 HIV ART 药物的血清蛋白结合也将为比较而确定。目标 2 将测定卡痛叶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，活性提取物或该化合物将使用作为 CYP 酶底物的一线和二线 HIV ART 药物进行重新测试，并计算表观内在间隙。本研究的预期结果是定量评估卡痛叶和 HIV ART CYP 底物之间的 PK 药物相互作用的研究。这些数据应该提供一个基本的了解 HIV ART 和卡痛叶之间的 PK 相互作用以及未来验证性临床的基本原理提高卡痛叶使用者中艾滋病毒抗逆转录病毒疗法的安全性和有效性的试验和方法。最终，洞察力这项研究应该改善患者和临床医生之间的教育和知识共享。