Enteric and hepatic transporter mechanisms for pharmacokinetic natural product-drug interactions

成立了天然产物-药物相互作用研究卓越中心(NaPDI Center)，以 选择、优先选择和研究4-6种具有潜在药代动力学的天然产物 产品-药物相互作用(NPDI)。这一努力是一项巨大的事业，取得了巨大的成功。 下面描述的绿茶和黄花的相互作用是由NaPDI中心和几个 对机制进行了假设和测试。最终，由于时间和预算的限制，主要的 机制还没有明确确定。NCCIH发出了进一步调查机制的具体要求 在这些互动中。这一要求为我们提供了一个独特的机会来完成这些机械数据 重要的NPDI。 2019年9月27日，NCCIH发送了一封电子邮件，重点介绍了与RFA-AT-20-001相关的两个感兴趣的领域。 这封电子邮件写道：“根据有关绿茶互动的最新数据，NCCIH对其他 更好地确定绿茶药代动力学相互作用的大小和意义的临床前研究 以及它的主要儿茶素成分和霉酚酸。这封电子邮件继续写道，“此外，还有 新出现的证据表明，植物黄花海豹的成分可能与 二甲双胍。因此，我们也对进一步的临床前研究感兴趣，以澄清与 观察到了黄花和二甲双胍之间的药代动力学相互作用。“ 这个应用程序将解决被组织成两个具体目标的两个假设：目标1：确定大小 以及绿茶与霉酚酸药代动力学相互作用的意义。假设--肠道和 肝脏有机阴离子转运多肽(OATP)摄取转运体负责绿茶- 诱导雷洛昔芬和霉酚酸全身暴露减少。目标2：澄清机制 与观察到的黄花和二甲双胍之间的药代动力学相互作用有关。假设--肠道 有机阳离子转运体(OCT)3是黄花引起的细胞内钙离子浓度下降的主要原因。 二甲双胍全身暴露。每个目标分为两项研究：研究1.1和2.1将确定体外 NPDI在过表达系统和Caco-2或肝细胞系统中的转运体动力学：研究1.2 和2.2将确定NPDI在临床可翻译小鼠体内的大小和意义 模特们。这项研究的完成将影响二甲双胍和霉酚酸的处方实践，以及 可扩展到作为这些肠道和肝脏转运蛋白底物的其他药物。

The Center of Excellence for Natural Product-Drug Interaction Research (NaPDI Center) was established to select, prioritize, and investigate 4-6 natural products with potential to perpetrate pharmacokinetic natural product-drug interactions (NPDIs). This effort was a massive undertaking that has been immensely successful. The green tea and goldenseal interactions described below were discovered by the NaPDI Center and several mechanisms were hypothesized and tested. Ultimately, due to time and budget constraints, the primary mechanisms were not definitively identified. NCCIH sent a specific request to further investigate the mechanisms of these interactions. This request provides us the unique opportunity to complete the mechanistic data for these important NPDIs. On September 27th, 2019 NCCIH sent an email highlighting two areas of interest pertaining to RFA-AT-20-001. The email stated, “Based on recent data on interactions involving green tea, NCCIH is interested in additional preclinical studies to better define the magnitude and significance of pharmacokinetic interactions of green tea and its major catechin constituents with mycophenolic acid.” The email continued, “Furthermore, there is emerging evidence that components of the botanical goldenseal have potentially significant interactions with metformin. Thus, we are also interested in further preclinical studies to clarify the mechanisms associated with observed pharmacokinetic interactions between goldenseal and metformin.” This application will address two hypotheses organized into two specific aims: Aim 1: Determine the magnitude and significance of pharmacokinetic interactions of green tea with mycophenolic acid. Hypothesis- Enteric and hepatic organic anion transporting polypeptide (OATP) uptake transporters are responsible for the green tea- induced decrease in raloxifene and mycophenolic acid systemic exposure. Aim 2: Clarify the mechanisms associated with observed pharmacokinetic interactions between goldenseal and metformin. Hypothesis- Enteric organic cation transporter (OCT)3 is predominantly responsible for the goldenseal-induced decrease in metformin systemic exposure. Each aim is divided into two studies: Studies 1.1 and 2.1 will determine the in vitro transporter kinetics of the NPDIs in overexpression systems and in Caco-2 or hepatocyte systems; Studies 1.2 and 2.2 will determine the in vivo magnitude and significance of the NPDIs in clinically translatable murine models. Completion of this research will impact prescribing practices for metformin and mycophenolic acid and may be extended to other drugs that are substrates for these enteric and hepatic transporters.