Pravastatin,an HMG-CoA Reductase Inhibitor,Is Transported by Rat Organic Anion Transporting Polypeptide,oatp2 |
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Authors: | Tokui Taro Nakai Daisuke Nakagomi Rie Yawo Hiromu Abe Takaaki Sugiyama Yuichi |
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Affiliation: | (1) Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, 140-8710, Japan;(2) Department of Neurophysiology, Tohoku University School of Medicine, Sendai, 980-8575, Japan;(3) Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-8654, Japan |
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Abstract: | Purpose. We previously demonstrated the HMG-CoA reductase inhibitor, pravastatin, is actively taken up into isolated rat hepatocytes through multispecific organic anion transporters. The present study examined whether a newly cloned organic anion transporting polypeptide (oatp2) transports pravastatin.Methods. We investigated functional expression of oatp2 in Xenopus laevis oocytes, to examine [14C] pravastatin uptake.Results. [14C] Pravastatin (30 M) uptake into oatp2 cRNA-injected oocytes was 40 times higher than that of water-injected control oocytes. The oatp2-mediated pravastatin uptake was Na+-independent and saturable. The Michaelis-Menten constant was 37.5 ± 9.9 M, a level comparable to that obtained in isolated rat hepatocytes in our previous study. As is the case with rat hepatocytes, the uptake of pravastatin (30 M) was inhibited by 300 M concentrations of taurocholate, cholate, bromosulfophthalein, estradiol-17-glucuronide, and simvastatin acid, but not by para-aminohippurate. On the other hand, [14C] simvastatin acid (30 M) uptake of oatp2 cRNA-injected oocytes was not significantly different from that of water-injected oocytes.Conclusions. The cloned oatp2 was identified as the transporter responsible for the active hepatocellular pravastatin uptake. |
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Keywords: | Pravastatin HMG-CoA reductase inhibitor organic anion transporter oatp2 hepatic transport |
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