Inhibition of hepatic uptake transporters by flavonoids

Members of the human SLC superfamily such as organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, and organic cation transporter 1 (OCT1) are drug uptake transporters that are localised on the basolateral membrane of hepatocytes mediating the uptake of drugs such as atorvastatin and metformin into hepatocytes. Ingredients of food such as flavonoids influence the effects of drugs, e.g. by inhibition of drug transporters. Therefore, we investigated the impact of the Ginkgo biloba flavonoids apigenin, kaempferol, and quercetin, and the grapefruit flavonoids naringenin, naringin, and rutin on the OATP1B1, OATP1B3, and OCT1 transport activity. Transporter expressing HEK293 cell lines were used with [3H]sulfobromophthalein ([3H]BSP) as substrate for OATP1B1 and OATP1B3, [3H]atorvastatin as substrate for OATP1B1, and [3H]1-methyl-4-phenylpyridinium ([3H]MPP(+)) as substrate for OCT1. The G. biloba flavonoids showed a competitive inhibition of the OATP1B1- and OATP1B3-mediated [3H]BSP and the OATP1B1-mediated [3H]atorvastatin uptake. Quercetin was the most potent inhibitor of the OATP1B1- and OATP1B3-mediated [3H]BSP transport with K(i)-values of 8.8±0.8μM and 7.8±1.7μM, respectively. For the inhibition of the OATP1B1-mediated [3H]atorvastatin transport, apigenin was the most potent inhibitor with a K(i) value of 0.6±0.2μM. Among the grapefruit flavonoids, naringenin was the most potent inhibitor of the OATP1B1- and OATP1B3-mediated [3H]BSP transport with IC(50)-values of 81.6±1.1μM and 101.1±1.1μM, respectively. All investigated flavonoids showed no significant inhibition of the OCT1-mediated [3H]MPP(+) uptake. Taken together, these in vitro studies showed that the investigated flavonoids inhibit the OATP1B1- and OATP1B3-mediated drug transport, which could be a mechanism for food-drug interactions in humans.