Evaluation of the potential of Ashwagandha extracts to produce CYP-mediated drug interactions.

评估 Ashwagandha 提取物产生 CYP 介导的药物相互作用的潜力。

• 批准号: 10271857
• 负责人: Robert D Arnold
• 金额: $ 7.45万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271857
• 关键词: Address; Adverse effects; Affect; Aging; Ashwagandha; Biological Assay; Botanical dietary supplements; Botanicals; CYP1A2 gene; CYP2B6 gene; CYP2C19 gene; CYP2C9 gene; CYP2D6 gene; CYP2E1 gene; CYP3A4 gene; Carrier Proteins; Chemicals; Clinical Research; Clinical Trials; Cognition; Cognitive; Complex; Cytochrome P450; Dangerousness; Data; Databases; Deposition; Drug Evaluation; Drug Interactions; Drug Kinetics; Elderly; Ensure; Enzymes; Euterpe; Evaluation; Funding; Future; Health; Health Sciences; Hepatic; Hepatocyte; Human; In Vitro; Investigation; Isoenzymes; Knowledge; Laboratories; Liver Microsomes; Measures; Mediating; Messenger RNA; Metabolism; Methanol; Natural Product Drug; Natural Products; Natural Products Chemistry; Neurologic; Nuclear Receptors; Oregon; Outcome; Peer Review; Pharmaceutical Preparations; Pharmacognosy; Pharmacy Schools; Phase; Pilot Projects; Plant Leaves; Plant Roots; Policies; Population; Protein Isoforms; Publications; Publishing; Reporting; Research; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sleep; Sleeplessness; Stress; Testing; Therapeutic Agents; Time; United States; United States National Institutes of Health; Universities; Veterinary Medicine; Work; age group; aqueous; base; college; dietary supplements; drug development; drug metabolism; enzyme activity; improved; mRNA Expression; novel therapeutics; resilience; response

Project Summary Although drug-drug interactions are routinely evaluated during new drug development, the potential for botanicals and botanical dietary supplements to cause natural product-drug interactions is rarely evaluated. To correct this deficiency, we are responding to the PAR-20-228: Pilot Projects Increasing the Impact of the NIH Centers for Advancing Research on Botanicals and Other Natural Products (PI2 CARBON). Specifically, we propose to evaluate Ashwagandha (Withania somnifera), one of the top 40 selling botanicals used by US consumers in 2018, for inhibition and induction of the most important Phase I drug metabolizing enzymes, the cytochromes P450 (CYPs). To date, there have been limited reports regarding the inhibitory effects of Ashwagandha extracts on the CYPs, and no published studies examined whether Ashwagandha extracts have the potential to induce CYP expression. Ashwagandha is used by older adults in particular to ameliorate stress, insomnia, and cognitive deficiencies; and this population is often taking conventional medications for other health conditions. Thus, use by the elderly makes a study of how Ashwagandha affects CYP activity and expression an important concern. Ashwagandha is one of two botanicals being studied for its ability to improve resilience in the BENFRA Botanical Dietary Supplements Research Center (BDSRC) at Oregon Health and Science University (U19 AT010829). Our work will synergize with that of the BENFRA BDSRC, which will provide authenticated and chemically characterized extracts of Ashwagandha roots and leaves for testing in the applicant’s laboratory at the University of Auburn. For our project, we propose two Specific Aims. In Aim 1, we will screen different types of Ashwagandha extracts for inhibition of 9 human hepatic CYPs (including all CYPs recommended for drug-drug evaluation by the FDA). Inhibition of CYPs in pooled human liver microsomes will be measured using CYP probe substrates and our ultrafast UHPLC-MS/MS cocktail assay. In Aim 2, we will assess induction of CYP mRNA expression caused by Ashwagandha extracts using primary human hepatocytes in sandwich culture according to the FDA Guidance on in vitro drug-drug interactions studies. The resulting comprehensive data of Ashwagandha extract-CYP interactions will be made available through scientific publications. Demonstration of inhibition or induction of CYPs by Ashwagandha will be followed by future studies that seek to identify the compounds responsible for the observed effects. Demonstration of interactions with CYP enzymes will be followed by confirmatory clinical studies of Ashwagandha-drug pharmacokinetic interactions.

项目摘要 尽管在新药开发期间常规评估了药物 - 药物相互作用，但 很少评估植物性和植物饮食补充剂，以引起天然产物 - 药物相互作用。到 纠正这种缺陷，我们正在响应Par-20-228：飞行员项目增加了NIH的影响 推进植物和其他天然产品（PI2碳）的研究中心。具体来说，我们 评估Ashwagandha（Withania Somnifera）的提议，这是我们使用的前40位销售植物之一 2018年的消费者，抑制和诱导了最重要的I期药物代谢酶， 细胞色素P450（CYPS）。迄今为止，关于抑制作用的报告有限 Ashwagandha提取了CYPS，没有发表的研究检查Ashwagandha提取物是否具有 诱导CYP表达的潜力。 Ashwagandha被老年人使用，特别是为了改善压力， 失眠和认知缺陷；而且这个人群经常为其他人服用常规药物 健康状况。这是对Ashwagandha如何影响CYP活动和 表达一个重要的问题。 Ashwagandha是研究其改进能力的两个植物学作品之一 俄勒冈州健康和 科学大学（U19 AT010829）。我们的工作将与Benfra BDSRC协同作用，这将 提供经过身份验证的化学表征提取物的Ashwagandha根和叶子以进行测试 奥本大学的申请人实验室。对于我们的项目，我们提出了两个具体目标。在AIM 1中， 我们将筛选不同类型的Ashwagandha提取物，以抑制9种人肝CYP（包括全部 FDA推荐用于药物毒品评估的CYP。抑制CYP在​​合并的人肝脏中 微粒体将使用CYP探针底物和我们的Ultrafast UHPLC-MS/MS鸡尾酒测定法测量。在 AIM 2，我们将评估使用主要的Ashwagandha提取物引起的CYP mRNA表达的诱导 根据FDA体外药物相互作用的指南，三明治培养中的人肝细胞 研究。将提供由Ashwagandha提取-CYP互动的最终综合数据 通过科学出版物。 Ashwagandha抑制或诱导CYP的证明将是 其次是未来的研究，试图识别负责观察到的影响的化合物。 与CYP酶相互作用的证明将进行确认性临床研究 Ashwagandha-drug药代动力学相互作用。