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: 10436380
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436380
• 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; National Center for Complementary and Integrative Health; 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.

项目概要 尽管在新药开发过程中会定期评估药物间相互作用，但潜在的 植物药和植物膳食补充剂引起天然产品-药物相互作用的研究很少被评估。到 为了纠正这一缺陷，我们正在响应 PAR-20-228：提高 NIH 影响力的试点项目 植物药和其他天然产品研究推进中心 (PI2 CARBON)。具体来说，我们 提议评估 Ashwagandha（Withania somnifera），美国最畅销的 40 种植物药之一 2018年，为了抑制和诱导最重要的一期药物代谢酶， 细胞色素 P450 (CYP)。迄今为止，关于其抑制作用的报道还很有限。 Ashwagandha 提取物对 CYP 的影响，并且没有发表的研究检验 Ashwagandha 提取物是否具有 诱导 CYP 表达的潜力。 Ashwagandha 特别被老年人用来缓解压力， 失眠和认知缺陷；该人群经常服用其他药物来治疗 健康状况。因此，老年人的使用研究了 Ashwagandha 如何影响 CYP 活性和 表达了一个重要的关切。 Ashwagandha 是正在研究的两种植物之一，其能够改善 俄勒冈州卫生局 BENFRA 植物膳食补充剂研究中心 (BDSRC) 的复原力 科学大学（U19 AT010829）。我们的工作将与 BENFRA BDSRC 的工作产生协同作用，后者将 提供经过验证和化学表征的 Ashwagandha 根和叶提取物，用于测试 申请人在奥本大学的实验室。对于我们的项目，我们提出了两个具体目标。在目标 1 中， 我们将筛选不同类型的 Ashwagandha 提取物对 9 种人肝 CYP 的抑制作用（包括所有 FDA 推荐用于药物间评价的 CYP）。混合人肝脏中 CYP 的抑制 将使用 CYP 探针底物和我们的超快 UHPLC-MS/MS 鸡尾酒测定来测量微粒体。在 目标 2，我们将使用初级评估 Ashwagandha 提取物引起的 CYP mRNA 表达诱导 根据 FDA 体外药物相互作用指南进行夹心培养的人肝细胞 研究。 Ashwagandha 提取物与 CYP 相互作用的综合数据将可供使用 通过科学出版物。 Ashwagandha 对 CYP 的抑制或诱导作用将被证明 接下来是未来的研究，旨在找出造成所观察到的影响的化合物。 与 CYP 酶相互作用的证明之后将进行验证性临床研究 Ashwagandha 药物药代动力学相互作用。