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Research ArticleMetabolism, Transport, and Pharmacogenomics

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Nathan D. Pfeifer, Kyunghee Yang and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics December 2013, 347 (3) 727-736; DOI: https://doi.org/10.1124/jpet.113.207472
Nathan D. Pfeifer
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Kyunghee Yang
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Kim L. R. Brouwer
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Abstract

Transporters responsible for hepatic uptake and biliary clearance (CLBile) of rosuvastatin (RSV) have been well characterized. However, the contribution of basolateral efflux clearance (CLBL) to hepatic and systemic exposure of RSV is unknown. Additionally, the appropriate design of in vitro hepatocyte efflux experiments to estimate CLBile versus CLBL remains to be established. A novel uptake and efflux protocol was developed in sandwich-cultured hepatocytes (SCH) to achieve desired tight junction modulation while maintaining cell viability. Subsequently, studies were conducted to determine the role of CLBL in the hepatic disposition of RSV using SCH from wild-type (WT) and multidrug resistance-associated protein 2 (Mrp2)-deficient (TR−) rats in the absence and presence of the P-glycoprotein and breast cancer resistance protein (Bcrp) inhibitor elacridar (GF120918). RSV CLBile was nearly ablated by GF120918 in TR− SCH, confirming that Mrp2 and Bcrp are responsible for the majority of RSV CLBile. Pharmacokinetic modeling revealed that CLBL and CLBile represent alternative elimination routes with quantitatively similar contributions to the overall hepatocellular excretion of RSV in rat SCH under baseline conditions (WT SCH in the absence of GF120918) and also in human SCH. Membrane vesicle experiments revealed that RSV is a substrate of MRP4 (Km = 21 ± 7 µM, Vmax = 1140 ± 210 pmol/min per milligram of protein). Alterations in MRP4-mediated RSV CLBL due to drug-drug interactions, genetic polymorphisms, or disease states may lead to changes in hepatic and systemic exposure of RSV, with implications for the safety and efficacy of this commonly used medication.

Footnotes

    • Received June 26, 2013.
    • Accepted September 3, 2013.
  • This study was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01GM41935]. N.D.P. was supported, in part, by the University of North Carolina Royster Society of Fellows.

  • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • A part of this work was presented at the following workshop: Pfeifer ND and Brouwer KLR (2013) A novel method to elucidate the relative contributions of basolateral efflux clearance versus biliary clearance of rosuvastatin in the sandwich-cultured hepatocyte model. American Association of Pharmaceutical Scientists (AAPS) Workshop on Drug Transporters in ADME; 18–20 March 2013; North Bethesda, MD.

  • dx.doi.org/10.1124/jpet.113.207472.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 347 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 3
1 Dec 2013
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Hepatic Basolateral Efflux of Rosuvastatin

Nathan D. Pfeifer, Kyunghee Yang and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 727-736; DOI: https://doi.org/10.1124/jpet.113.207472

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Hepatic Basolateral Efflux of Rosuvastatin

Nathan D. Pfeifer, Kyunghee Yang and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 727-736; DOI: https://doi.org/10.1124/jpet.113.207472
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