title: Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans.
abstract: Pitavastatin, a novel potent 3-hydroxymethylglutaryl-CoA reductase inhibitor, is selectively distributed to the liver in rats. However, the hepatic uptake mechanism of pitavastatin has not been clarified yet. In the present study, we investigated the contribution of organic anion transporting polypeptide 2 (OATP2/OATP1B1) and OATP8 (OATP1B3) to pitavastatin uptake using transporter-expressing HEK293 cells and human cryopreserved hepatocytes. Uptake studies using OATP2- and OATP8-expressing cells revealed a saturable and Na(+)-independent uptake, with K(m) values of 3.0 and 3.3 microM for OATP2 and OATP8, respectively. To determine which transporter is more important for its hepatic uptake, we proposed a methodology for estimating their quantitative contribution to the overall hepatic uptake by comparing the uptake clearance of pitavastatin with that of reference compounds (a selective substrate for OATP2 (estrone-3-sulfate) and OATP8 (cholecystokinin octapeptide) in expression systems and human hepatocytes. The concept of this method is similar to the so-called relative activity factor method often used in estimating the contribution of each cytochrome P450 isoform to the overall metabolism. Applying this method to pitavastatin, the observed uptake clearance in human hepatocytes could be almost completely accounted for by OATP2 and OATP8, and about 90% of the total hepatic clearance could be accounted for by OATP2. This result was also supported by estimating the relative expression level of each transporter in expression systems and hepatocytes by Western blot analysis. These results suggest that OATP2 is the most important transporter for the hepatic uptake of pitavastatin in humans.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Hirano
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shitara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D001692:Biological Transport; D015153:Blotting, Western; D002478:Cells, Cultured; D004347:Drug Interactions; D004970:Estrone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D011804:Quinolines / Q000493:pharmacokinetics*; D012844:Sincalide / Q000493:pharmacokinetics; D012964:Sodium / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; D011804:Quinolines; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D004970:Estrone; D012964:Sodium; D012844:Sincalide; C108475:pitavastatin; C017296:estrone sulfate