Vol. 292, Issue 2, 505-511, February 2000

Characterization of the Transport Properties of Organic Anion Transporting Polypeptide 1 (oatp1) and Na⁺/Taurocholate Cotransporting Polypeptide (Ntcp): Comparative Studies on the Inhibitory Effect of their Possible Substrates in Hepatocytes and cDNA-Transfected COS-7 Cells

Hirokazu Kouzuki, Hiroshi Suzuki , Bruno Stieger, Peter J. Meier and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K., H.S., Y.S.); The Core Research for Evolutional Sciences and Technology (CREST), Japan Science and Technology Corporation (JST) (H.S., Y.S.); and Department of Medicine, Division of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland (B.S., P.J.M.).

In the present study, we compared the inhibitory effects of organic anions (including bile acids) on the uptake of taurocholate (TC) and estradiol 17-D-glucuronide (E₂17G), typical substrates for sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide (oatp1), respectively, using primary cultured rat hepatocytes and Ntcp- or oatp1-transfected COS-7 cells. The Na⁺-dependent uptake of TC was inhibited by nine bile acids and five nonbile acid organic anions in a concentration-dependent manner, and their inhibitory effects were similar in both primary cultured rat hepatocytes and Ntcp-transfected COS-7 cells. BQ-123 (1 µM) and indomethacin (10 µM), both of which exhibit no Ntcp-mediated transport, significantly inhibited the Na⁺-dependent uptake of TC mediated by Ntcp. In addition, the Na⁺-independent uptake of E₂17G was inhibited by 15 organic anions in a concentration-dependent manner, and their inhibitory effects were similar between primary cultured rat hepatocytes and oatp1-transfected COS-7 cells. BQ-123 (1 µM), pravastatin (1 µM), and indomethacin (10 µM), all of which do not undergo oatp1-mediated transport, significantly inhibited the Na⁺-independent uptake of E₂17G mediated by oatp1. These results are consistent with the hypothesis that the hepatic uptake of TC and E₂17G is predominantly mediated by Ntcp and oatp1, respectively. In addition, it was clearly demonstrated that we cannot refer to the substrate specificity of transporters based on inhibition studies.