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中心）， 选择，优先考虑，并调查4-6天然产品有可能犯药代动力学自然 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。 下面描述的绿色茶和白毛茛的相互作用是由NaPDI中心和几个 机制进行了假设和测试。最终，由于时间和预算的限制， 机制尚未确定。国家刑事调查委员会发出了进一步调查这些机制的具体请求。 这些互动。这一要求为我们提供了一个独特的机会，以完成这些机械数据， 重要的NPD。 2019年9月27日，NCCIH发送了一封电子邮件，强调了与RFA-AT-20-001有关的两个感兴趣的领域。 电子邮件指出，“根据最近关于绿色茶相互作用的数据，NCCIH对其他的 临床前研究，以更好地确定绿色茶的药代动力学相互作用的程度和意义 和它的主要儿茶素成分麦考酚酸。”电子邮件继续说，“此外， 新出现的证据表明，植物性白毛茛的成分与 二甲双胍。因此，我们也有兴趣在进一步的临床前研究，以澄清相关的机制， 观察到了毛茛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两个假设组织成两个具体的目标：目标1：确定幅度 绿色茶与霉酚酸的药代动力学相互作用及其意义。假设-肠和 肝脏有机阴离子转运多肽（OATP）摄取转运蛋白负责绿色茶- 诱导雷洛昔芬和麦考酚酸全身暴露减少。目标2：澄清机制 与观察到的goldenseal和二甲双胍之间的药代动力学相互作用相关。假设-肠道 有机阳离子转运蛋白（OCT）3主要负责金叶菊诱导的 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蛋白动力学;研究1.2 和2.2将确定临床上可翻译的鼠中NPDI的体内大小和意义 模型这项研究的完成将影响二甲双胍和麦考酚酸的处方实践， 可以扩展到作为这些肠和肝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.