Assessing Transporter-Mediated Natural Product-Drug Interactions Using a Translational Research Approach

使用转化研究方法评估转运蛋白介导的天然产物-药物相互作用

• 批准号: 10315518
• 负责人: James T Nguyen
• 金额: $ 3.75万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2023-12-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315518
• 关键词: Alkaloids; Antidiabetic Drugs; Apical; Berberine; Biological Assay; Botanical dietary supplements; Botanicals; Caco-2 Cells; Cell Line; Cells; Clinic; Clinical; Clinical Research; Consumption; Coupled; Data; Development; Drug Interactions; Drug Kinetics; Education; Enzymes; Epithelial Cells; Exposure to; Fasting; Goldenseal; Half-Life; Health; Healthcare; Hospitalization; Human; In Vitro; Intestines; Knowledge; Lead; Liquid substance; Literature; Mediating; Membrane; Metabolism; Metformin; Methods; Modeling; Natural Product Drug; Natural Products; OATP Transporters; Organic Cation Transporter; Organic Cation Transporter 1; POU2F1 gene; Permeability; Pharmaceutical Preparations; Pharmacology; Physiological; Plasma; Preparation; Process; Property; Proteins; Recommendation; Renal clearance function; Reporting; Research Project Grants; Risk; Sales; Solubility; Standardization; System; Testing; Therapeutic Equivalency; Time; Tissues; Toxic effect; Toxin; Translational Research; Type 2 diabetic; United States; Vesicle; absorption; base; clinical effect; clinically relevant; cost; diabetic; diabetic patient; dietary supplements; evidence base; follow-up; healthy volunteer; hydrastine; in vitro Assay; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; models and simulation; monolayer; overexpression; patient population; pharmacokinetic model; population based; predictive modeling; refractory cancer; rosuvastatin; uptake; virtual

PROJECT SUMMARY Sales of botanical dietary supplements in the United States have steadily increased since passage of the Dietary Supplement Health and Education act in 1994, nearing $10 billion annually as of 2019. As sales of these natural products continue to rise, the need to characterize the risk of co-consuming them with conventional drugs is imperative. Like drug-drug interactions, common pharmacokinetic mechanisms underlying natural product-drug interactions include inhibition of drug metabolizing enzymes and/or transporters by the precipitant natural product. Such interactions lead to altered systemic and/or tissue exposure to the object drug, which can result in suboptimal pharmacologic or toxic effects. Unlike for drug-drug interactions, recommended approaches for assessing pharmacokinetic natural product-drug interactions remain scarce, particularly for transporter-mediated interactions. Results from the applicant’s recent clinical pharmacokinetic study showed that the botanical dietary supplement goldenseal significantly decreased the systemic exposure to the anti-diabetic drug metformin in healthy volunteers (by 23%). This compelling observation, along with complementary data from cell-based transporter inhibition assays, the working hypothesis is that goldenseal inhibits the uptake transporter organic cation transporter (OCT) 1 in the intestine to reduce metformin absorption. Based on the collective evidence, a set of follow-up mechanistic studies is proposed that involve established in vitro systems, physiologically-based pharmacokinetic (PBPK) modeling and simulation, and a proof-of-concept clinical study in a relevant patient population (type 2 diabetics). Solubility and permeability parameters for the major alkaloids (berberine and (−)- β-hydrastine) typically present in goldenseal products will be determined using simulated human intestinal fluids and Caco-2 cell monolayers, respectively. These experimentally obtained absorption parameters, along with other input parameters obtained from the literature, will be incorporated into a mechanistic PBPK model, which will integrate intestinal OCT1 with other metformin-relevant transporters, to further characterize the goldenseal- metformin interaction. An established dissolution/absorption/metabolism model will be used as the framework to develop the PBPK model, which will allow for greater mechanistic insights into potential changes in intestinal processes when virtual diabetic subjects are exposed to goldenseal products. A clinical study will then be conducted to verify model prediction accuracy and to determine the clinical relevance of these pharmacokinetic changes in type 2 diabetic patients. The proposed translational project will be the first of its kind to develop a PBPK model for elucidating transporter-mediated natural product-drug interactions. The knowledge gained from these efforts will ultimately build upon a systematic framework for effectively studying other potential transporter- mediated natural product-drug interactions.

项目摘要 自《膳食补充剂法》通过以来，美国植物膳食补充剂的销售稳步增长。 1994年的补充健康和教育法案，截至2019年每年接近100亿美元。作为销售这些自然 产品继续上升，需要描述与常规药物共同消费的风险， 势在必行与药物相互作用一样，天然产物-药物相互作用的常见药代动力学机制 相互作用包括沉淀剂天然存在对药物代谢酶和/或转运蛋白的抑制 产品这样的相互作用导致改变的全身和/或组织暴露于目标药物，这可以导致 药理学或毒性效果欠佳。与药物相互作用不同， 评估药代动力学天然产物-药物相互作用仍然很少，特别是对于转运蛋白介导的 交互.申请人最近的临床药代动力学研究结果表明， 补充goldenseal显着降低了抗糖尿病药物二甲双胍的全身暴露， 健康志愿者（23%）。这一令人信服的观察，沿着补充数据，从细胞为基础的 转运蛋白抑制试验中，工作假设是，毛茛抑制摄取转运蛋白有机 阳离子转运蛋白（OCT）1，以减少二甲双胍的吸收。根据集体证据， 一组后续机制研究建议，涉及建立在体外系统，生理为基础的 药代动力学（PBPK）建模和模拟，以及相关患者的概念验证临床研究 人群（2型糖尿病患者）。主要生物碱（小檗碱和（−）- 将使用模拟人肠液测定通常存在于白毛茛产品中的β-海斯汀 和Caco-2细胞单层。这些实验获得的吸收参数，沿着 从文献中获得的其他输入参数，将被纳入一个机制PBPK模型， 将整合肠道OCT 1与其他二甲双胍相关转运蛋白，以进一步表征白毛茛- 二甲双胍相互作用。将使用已建立的溶出/吸收/代谢模型作为框架， 开发PBPK模型，这将允许更深入地了解肠道的潜在变化， 当虚拟的糖尿病患者接触到goldenseal产品时，然后将进行临床研究， 进行验证模型预测准确性，并确定这些药代动力学的临床相关性 2型糖尿病患者的变化。拟议的翻译项目将是第一个开发一个 用于阐明转运蛋白介导的天然产物-药物相互作用的PBPK模型。知识来自于 这些努力最终将建立在有效研究其他潜在转运体的系统框架之上， 介导的天然产物-药物相互作用。