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Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin.
Drug Metab Dispos. 2008 Oct; 36(10):2014-23.DM

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.

Authors+Show Affiliations

Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18617601

Citation

Kitamura, Satoshi, et al. "Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 36, no. 10, 2008, pp. 2014-23.
Kitamura S, Maeda K, Wang Y, et al. Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008;36(10):2014-23.
Kitamura, S., Maeda, K., Wang, Y., & Sugiyama, Y. (2008). Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 36(10), 2014-23. https://doi.org/10.1124/dmd.108.021410
Kitamura S, et al. Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin. Drug Metab Dispos. 2008;36(10):2014-23. PubMed PMID: 18617601.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. AU - Kitamura,Satoshi, AU - Maeda,Kazuya, AU - Wang,Yi, AU - Sugiyama,Yuichi, Y1 - 2008/07/10/ PY - 2008/7/12/pubmed PY - 2008/12/23/medline PY - 2008/7/12/entrez SP - 2014 EP - 23 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 36 IS - 10 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/18617601/Involvement_of_multiple_transporters_in_the_hepatobiliary_transport_of_rosuvastatin_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18617601 DB - PRIME DP - Unbound Medicine ER -