Although there are many suggestions for the contribution of efflux transporters in intestinal secretion/barrier of drugs mediated by ABC transporter, information on the absorptive/influx transporter molecules responsible for the intestinal absorptive process is limited. Organic anion transporting polypeptides (OATP; SLCO) family is expressed in various tissues including intestine and liver (1). OATP1B1 and OATP1B3 are selectively expressed in liver basolateral membrane thereby contributing in hepatic uptake of xeno- and endo-biotics such as bile acids and conjugated metabolites of bilirubin and steroids hormones. Those OATPs accept clinically used drugs such as statins and others. Effect of genetic polymorphism of OATP1B1, which cause altered activity, on pharmacokinetics of its substrate drugs clarified in vivo significance of OATP1B1(1). Accordingly, based on such a pharmacological relevance, OATPs are well recognized as physiologically and pharmacologically important transporters. OATP molecules are expressed in intestine and we tried to clarify its role in intestinal absorption of drugs. OATP2B1 (OATP-B, SLCO2B1) is expressed at the apical membrane of human intestinal epithelial cells and accepts similar compounds with hepatic OATPs as substrates (2,3). Accordingly, it is possible that OATP2B1 may drug absorption due to its broad substrate selectivity, while it is not easy to demonstrate its in vivo relevance to intestinal absorption. We found that genetic variant SLCO2B1*3, which has mutation c.1457>T that causes the amino acid change S486F, showed a decreased transport activity of estrone-3-sulfate (E3S), which is a physiological substrate of OATP2B1 (3). Fexofenadine (FEX), an anti-allergic agent is a substrate of OATP2B1, and OATP2B1 was thought to be the mechanism of its intestinal absorption, while there was no evidence of in vivo contribution of OATP2B1. Accordingly, we tested effect of genotype, SLCO2B1*3 (c.1457>T), on intestinal absorption of FEX after oral administration (3). As the results AUCs in individuals with genotype TT showed lowest plasma exposure of FEX, demonstrating in vivo contribution of OATP2B1 in the drug absorption. Another evidence of in vivo relevance of OATP2B1 was obtained by interaction of FEX absorption with fruit juices (FJ). When taking drugs orally with grapefruit juice (GFJ) and apple juice (AJ), plasma concentrations of substrate drugs of OATP2B1, including FEX and beta-adrenergic receptor antagonist talinolol, are affected (3). When examined inhibitory effect of those FJ on OATP2B1 by in vitro OATP2B1-expressing cultured cells, all FJs decreased apparent uptake of E3S via OATP2B1 at diluted concentration lower than 10% (4). These in vitro FJ effects strongly suggest that OATP2B1 is responsible for drug absorption. Further studies suggested that the responsible components in GFJ as inhibitors include naringin, hesperidin and others, while it was not clear in AJ. However, by uptake studies using in vitro OATP2B1-expressed cells, naringin showed differential inhibitory effect depending on used substrates, demonstrating substrate selective inhibitory effect. In addition, concentration dependence in E3S uptake by OATP2B1 showed biphasic kinetics. Therefore, it is possible that there are multiple binding sites (MBS) on OATP2B1 which show different substrate and inhibitor selectivity (5). MBS may cause dose/concentration dependence by mainly contributing binding sites on OATP2B1. Accordingly, MBS hypothesis may explain apparently discrepant in vitro and in vivo observations as well as broad substrate selectivity of OATP2B1. More interestingly, AJ but not GFJ decreased OATP2B1 activity even by only preincubation without co-existence during uptake measurement, namely long-lasting effect (6). Although the mechanism of long-lasting effect of AJ is not clear, it is known that OATP2B1 protein is internalized by protein-kinase C activation, thereby showing reduction of apparent uptake activity (7). When we exposed OATP2B1-expressing cultured cells with AJ and analyzed protein localization using antibody, intracellular localization was apparently changed by exposing with AJ. Accordingly, AJ effect might be explained by altered intracellular localization of OATP2B1 protein. In conclusion, OATP2B1 should be responsible for absorption of various compounds including clinically used drugs. MBS may contribute to a broad substrate specificity of OATP2B1. In addition, clinical observation in OATP2B1-mediated absorption and interaction may be complex due to MBS and change in trafficking of OATP2B1 proteins by any co-administered drugs or food/juice. Most of information on OATP2B1, especially in vivo observation, came from the studies using drugs. According utilization of clinically used drugs as probes to monitor transporter activity is useful.