Integrated approaches to identify and predict pharmacokinetic-based dietary substance-drug interactions.

摘要

The large variation in bioactive ingredient composition inherent to natural products, including dietary substances, can confound the design and interpretation of natural product-drug interaction studies. The purpose of this dissertation was to address this overlooked issue by developing a framework to evaluate pharmacokinetic-based dietary substance-drug interactions such that ultimately, firm clinical recommendations can be made. Fruit juices represent a diverse market of popular foods containing phytochemicals that can inhibit drug metabolizing enzymes and transporters in the intestine. The potential increase or decrease in systemic drug exposure could lead to adverse effects or therapeutic failure, respectively. A multi-experimental approach utilizing in vitro (bioactivity-guided fractionation), in vivo (clinical study), and in silico (modeling and simulation) methods was applied to the exemplar dietary substance grapefruit juice (GFJ). GFJ has been shown to inhibit oral absorption of certain drugs that require the uptake transporter family of organic anion transporting polypeptides (OATPs) located in the intestine. The inhibitory effects of GFJ and a unique food-grade GFJ devoid of two classes of candidate OATP inhibitors, furanocoumarins and polymethoxyflavones, on intestinal OATP activity were evaluated in OATP1A2- and OATP2B1-transfected cells and in healthy volunteers. Results from the in vitro study were predictive of the in vivo study, demonstrating that furanocoumarins and polymethoxyflavones do not contribute to intestinal OATP inhibition. Bioactivity-guided fractionation of GFJ using estrone 3-sulfate as a probe substrate and OATP2B1-transfected cells yielded several potent groups of OATP2B1 inhibitors. GFJ also has been shown to inhibit the metabolism of drugs that require the cytochrome P450 3A4 (CYP3A4) enzyme in the intestine. A population-based modeling and simulation program incorporating in vitro and in vivo data from the literature evaluated two furanocoumarins, 6',7'-dihydroxybergamottin and bergamottin, as candidate marker compounds predictive of the GFJ effect on select CYP3A4 drug substrates. Results from the in silico study supported both furanocoumarins as potential marker compounds. These integrated approaches address the challenges of, and begin to establish best practices for, the study of dietary substance-drug interactions. Such research methods must be refined and reinforced as concomitant intake of new (and older) natural products and drugs continues to rise.