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Research ArticleArticle

Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin

Satoshi Kitamura, Kazuya Maeda, Yi Wang and Yuichi Sugiyama
Drug Metabolism and Disposition October 2008, 36 (10) 2014-2023; DOI: https://doi.org/10.1124/dmd.108.021410
Satoshi Kitamura
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Kazuya Maeda
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Yi Wang
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Yuichi Sugiyama
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Abstract

Rosuvastatin is an HMG-CoA reductase inhibitor and one of the most hydrophilic among the commercially available statins. It is efficiently accumulated in the liver and excreted into the bile in an unchanged form in rats, suggesting that hepatic transporters play a major role in its clearance. Therefore, we investigated the transporters responsible for the hepatic uptake and biliary excretion of rosuvastatin. Uptake studies revealed that human organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 accept rosuvastatin as a substrate. Among the OATP family transporters, OATP1B1 contributes predominantly to the hepatic uptake of rosuvastatin, as estimated with the previously published relative activity factor method, and OATP1B3 is also partly involved. Significant vectorial basal-to-apical transport was observed in OATP1B1/multidrug resistance-associated protein 2 (MRP2), OATP1B1/multidrug resistance protein 1 (MDR1), and OATP1B1/breast cancer resistance protein (BCRP) double transfectants compared with that in an OATP1B1 single transfectant or in vector-transfected control cells. The ATP-dependent uptake of rosuvastatin by human BCRP-expressing membrane vesicles was significantly higher than the uptake by green fluorescent protein-expressing control vesicles, suggesting that MRP2, MDR1, and BCRP can transport rosuvastatin. Under in vivo conditions, the biliary excretion clearances based on the intrahepatic concentration of the parent rosuvastatin in Eisai hyperbilirubinemic rats and Bcrp1 knockout mice were reduced to 53% and 12% of those in the control Sprague-Dawley rats and FVB mice, respectively, indicating that rat Mrp2 and mouse Bcrp1 are both partly involved in the biliary excretion of rosuvastatin. These results suggest that multiple transporters are involved in the hepatic uptake and efflux of rosuvastatin.

Footnotes

  • This study was supported by Labor Sciences Research Grants from the Ministry of Health, Labor, and Welfare for research on toxicogenomics and a Grant-in-Aid for Young Scientists (B) (19790119) from the Ministry of Education, Culture, Sports, Science and Technology.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.021410.

  • ABBREVIATIONS: OATP, organic anion transporting polypeptide; NTCP, sodium-taurocholate cotransporting polypeptide; MRP, multidrug resistance-associated protein; MDR, multidrug resistance protein; BCRP/Bcrp, breast cancer resistance protein; SD, Sprague-Dawley; EHBR, Eisai hyperbilirubinemic rat; E1S, estrone-3-sulfate; E217βG, 17β-estradiol-17β-d-glucuronide; CCK-8, cholecystokinin octapeptide; HEK, human embryonic kidney; MDCK, Madin-Darby canine kidney; GFP, green fluorescent protein; TLC, thin-layer chromatography; SNP, single nucleotide polymorphism.

    • Received March 11, 2008.
    • Accepted July 7, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (10)
Drug Metabolism and Disposition
Vol. 36, Issue 10
1 Oct 2008
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Research ArticleArticle

Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin

Satoshi Kitamura, Kazuya Maeda, Yi Wang and Yuichi Sugiyama
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2014-2023; DOI: https://doi.org/10.1124/dmd.108.021410

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Research ArticleArticle

Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin

Satoshi Kitamura, Kazuya Maeda, Yi Wang and Yuichi Sugiyama
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2014-2023; DOI: https://doi.org/10.1124/dmd.108.021410
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