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

项目总结 自《膳食法案》通过以来，美国植物性膳食补充剂的销量稳步增长 《补充健康和教育法案》于1994年颁布，截至2019年，该法案每年的资金接近100亿美元。随着这些天然产品的销售 产品继续上升，需要描述与传统药物共同消费它们的风险是 势在必行。与药物-药物相互作用一样，天然产物-药物的共同药代动力学机制 相互作用包括通过沉淀剂天然抑制药物代谢酶和/或转运蛋白 产品。这种相互作用导致全身和/或组织暴露于目标药物的改变，这可能导致 在次优的药理或毒性作用中。与药物-药物相互作用不同，推荐的方法是 评估药代动力学天然产物-药物相互作用仍然很少，特别是对转运体介导的 互动。申请人最近的临床药代动力学研究结果表明，植物性饮食 补充黄花可显著减少体内抗糖尿病药物二甲双胍的全身暴露。 健康志愿者(增加23%)。这一令人信服的观察结果，以及基于细胞的补充数据 转运蛋白抑制试验，工作假说是黄花丹有机地抑制摄取转运蛋白 肠道中的阳离子转运蛋白(OCT)1可减少二甲双胍的吸收。根据集体证据， 提出了一套后续机制研究，涉及建立基于生理的体外系统 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(黄连素和(−)-)的溶解度和渗透性参数 β-hystine)将使用模拟的人体肠液进行测定 和Caco-2细胞单层。这些通过实验获得的吸收参数，以及 从文献中获得的其他输入参数将被合并到机械性PBPK模型中，该模型 将整合肠道OCT1与其他二甲双胍相关的转运蛋白，以进一步表征黄金海豹- 二甲双胍相互作用。已建立的溶出/吸收/代谢模型将被用作框架 开发PBPK模型，这将允许对肠道潜在变化的更大机械性洞察 当虚拟糖尿病受试者接触到金海豹产品时的过程。然后将进行临床研究 进行以验证模型预测的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此类项目中第一个开发 用于阐明转运体介导的天然产物-药物相互作用的PBPK模型。从以下方面获得的知识 这些努力最终将建立在一个系统框架的基础上，以便有效地研究其他潜在的运输者- 调节天然产物与药物的相互作用。

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.