Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1

Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Fahrstraße 17, 91054 Erlangen, Germany.
Biochemical pharmacology (Impact Factor: 5.01). 12/2010; 80(11):1746-53. DOI: 10.1016/j.bcp.2010.08.008
Source: PubMed


OATP1A2 and OATP2B1 are uptake transporters of the human organic anion transporting polypeptide (OATP) family with a broad substrate spectrum including several endogenous compounds as well as drugs such as the antihistaminic drug fexofenadine and HMG-CoA reductase inhibitors. Both transporters are localized in the apical membrane of human enterocytes. Flavonoids, abundantly occurring in plants, have previously been shown to interact with drug metabolizing enzymes and transporters. However, the impact of flavonoids on OATP1A2 and OATP2B1 transport function has not been analyzed in detail. Therefore, HEK293 cell lines stably expressing OATP1A2 and OATP2B1 were used to investigate the influence of the Ginkgo flavonoids apigenin, kaempferol, and quercetin on the transport activity of OATP1A2 and OATP2B1. K(i) values of all three flavonoids determined from Dixon plot analyses using BSP as substrate indicated a competitive inhibition with quercetin as the most potent inhibitor of OATP1A2 (22.0μM) and OATP2B1 (8.7μM) followed by kaempferol (OATP1A2: 25.2μM, OATP2B1: 15.1μM) and apigenin (OATP1A2: 32.4μM OATP2B1: 20.8μM). Apigenin, kaempferol, and quercetin led to a concentration-dependent decrease of the OATP1A2-mediated fexofenadine transport with IC(50) values of 4.3μM, 12.0μM, and 12.6μM, respectively. The OATP1A2- and OATP2B1-mediated transport of atorvastatin was also efficiently inhibited by apigenin (IC(50) for OATP1A2: 9.3μM, OATP2B1: 13.9μM), kaempferol (IC(50) for OATP1A2: 37.3μM, OATP2B1: 20.7μM) and quercetin (IC(50) for OATP1A2: 13.5μM, OATP2B1: 14.1μM). These data indicate that modification of OATP1A2 and OATP2B1 transport activity by apigenin, kaempferol, and quercetin may be a mechanism for food-drug or drug-drug interactions in humans.

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Available from: Werner Siegmund, Jan 06, 2014
    • "All investigated flavonoids inhibited OATP1B1 and OATP1B3 in vitro to different extent. For the G. biloba flavonoids a competitive mechanism of inhibition could be determined, as previously shown for OATP1A2 and OATP2B1 (Mandery et al., 2010). Quercetin was an inhibitor, which could reach high portal venous concentrations and may therefore be able to cause drug–food interactions. "
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    ABSTRACT: 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.
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    • "Hesperidin, a major component of orange juice, is a flavonoid glycoside with a molecular structure similar to that of naringin [151]. Hesperidin has been shown to inhibit OATP1A2- mediated uptake of fexofenadine in vitro, with an IC 50 of 2.7 μM [61], similar to that of naringin (3.6 μM). "
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