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

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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.