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.

项目总结