Tuesday, March 28, 2023
3/28/2023
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 (-)- ß-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.
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