bergamottin and estrone-sulfate

Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health-care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells (Madin-Darby canine kidney type II) and the probe substrate estrone 3-sulfate, IC

Topics: Animals; Cells, Cultured; Citrus paradisi; Computer Simulation; Dogs; Estrone; Flavanones; Flavones; Food-Drug Interactions; Fruit and Vegetable Juices; Furocoumarins; Hesperidin; Humans; Inhibitory Concentration 50; Models, Biological; Organic Anion Transporters

Human organic anion-transporting polypeptide B (OATP-B; OATP2B1) is expressed in the human intestinal epithelial cells, and is suggested to be involved in the intestinal absorption of anionic drugs in vivo. Although citrus juices have been shown to inhibit the function of human OATP-A (OATP1A2), the effect of citrus juices on the OATP-B function remains unclear. In this study, we aimed to examine the effects of citrus juices on the function of OATP-B. The effects of citrus juices on the uptake of estrone-3-sulfate, a typical substrate for OATP-B, into human embryonic kidney 293 cells stably expressing OATP-B were evaluated. Juices were diluted with uptake buffer, adjusted to pH 7.4 and approximately 300 mOsm, and used for the experiments. Grapefruit juice (GFJ) and orange juice (OJ) at a concentration of 5% significantly inhibited the OATP-B-mediated uptake of estrone-3-sulfate by 82 and 53%, respectively. Major constituents of GFJ and OJ also significantly inhibited the OATP-B-mediated uptake of estrone-3-sulfate. Glibenclamide, a hypoglycemic drug, was identified for the first time as a substrate for OATP-B with a K(t) value of 6.26 microM. GFJ and OJ inhibited the OATP-B-mediated uptake of glibenclamide. These results suggest that citrus juices may inhibit the intestinal absorption of anionic drugs, such as glibenclamide, via the inhibition of OATP-B.

Topics: Beverages; Cell Line; Citrus paradisi; Citrus sinensis; Estrone; Glyburide; Humans; Organic Anion Transporters; Transfection