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Research ArticleMetabolism, Transport, and Pharmacogenomics

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition II: Characterization of Hepatic Elimination by Basolateral, Biliary, and Metabolic Clearance Pathways in Rat Isolated Perfused Liver

Nathan D. Pfeifer, Arlene S. Bridges, Brian C. Ferslew, Rhiannon N. Hardwick and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics December 2013, 347 (3) 737-745; DOI: https://doi.org/10.1124/jpet.113.208314
Nathan D. Pfeifer
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina (N.D.P., B.C.F., K.L.R.B.); and Department of Pathology (A.S.B.) and Curriculum in Toxicology (R.N.H., K.L.R.B.), School of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Arlene S. Bridges
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina (N.D.P., B.C.F., K.L.R.B.); and Department of Pathology (A.S.B.) and Curriculum in Toxicology (R.N.H., K.L.R.B.), School of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Brian C. Ferslew
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina (N.D.P., B.C.F., K.L.R.B.); and Department of Pathology (A.S.B.) and Curriculum in Toxicology (R.N.H., K.L.R.B.), School of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Rhiannon N. Hardwick
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina (N.D.P., B.C.F., K.L.R.B.); and Department of Pathology (A.S.B.) and Curriculum in Toxicology (R.N.H., K.L.R.B.), School of Medicine, UNC School of Medicine, 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, Chapel Hill, North Carolina (N.D.P., B.C.F., K.L.R.B.); and Department of Pathology (A.S.B.) and Curriculum in Toxicology (R.N.H., K.L.R.B.), School of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Abstract

Basolateral efflux clearance (CLBL) contributes significantly to rosuvastatin (RSV) elimination in sandwich-cultured hepatocytes (SCH). The contribution of CLBL to RSV hepatic elimination was determined in single-pass isolated perfused livers (IPLs) 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); clearance values were compared with SCH. RSV biliary clearance (CLBile) was ablated almost completely by GF120918 in TR− IPLs, confirming that Mrp2 and Bcrp primarily are responsible for RSV CLBile. RSV appearance in outflow perfusate was attributed primarily to CLBL, which was impaired in TR− IPLs. CLBL was ∼6-fold greater than CLBile in the linear range in WT IPLs in the absence of GF120918. Recovery of unchanged RSV in liver tissue increased in TR− compared with WT (∼25 versus 6% of the administered dose) due to impaired CLBL and CLBile. RSV pentanoic acid, identified by high-resolution liquid chromatography–tandem mass spectroscopy, comprised ∼40% of total liver content and ∼16% of the administered dose in TR− livers at the end of perfusion, compared with ∼30 and 3% in WT livers, consistent with impaired RSV excretion and “shunting” to the metabolic pathway. In vitro–ex vivo extrapolation between WT SCH and IPLs (without GF120918) revealed that uptake clearance and CLBL were 4.2- and 6.4-fold lower, respectively, in rat SCH compared with IPLs; CLBile translated almost directly (1.1-fold). The present IPL data confirmed the significant role of CLBL in RSV hepatic elimination, and demonstrated that both CLBL and CLBile influence RSV hepatic and systemic exposure.

Footnotes

    • Received July 30, 2013.
    • Accepted September 30, 2013.
  • This research was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM41935] (to K.L.R.B); and National Institutes of Health National Institute of Environmental Health Sciences [Grant T32 ES007126] (training grant to R.N.H.). This work is based upon research supported in whole or in part by the North Carolina Biotechnology Center [Institutional Development Grant 2012-IDG-1008] (to the UNC Eshelman School of Pharmacy). 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. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views and policies of the North Carolina Biotechnology Center.

  • dx.doi.org/10.1124/jpet.113.208314.

  • 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

Rosuvastatin Disposition in Rat Isolated Perfused Liver

Nathan D. Pfeifer, Arlene S. Bridges, Brian C. Ferslew, Rhiannon N. Hardwick and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 737-745; DOI: https://doi.org/10.1124/jpet.113.208314

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Rosuvastatin Disposition in Rat Isolated Perfused Liver

Nathan D. Pfeifer, Arlene S. Bridges, Brian C. Ferslew, Rhiannon N. Hardwick and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 737-745; DOI: https://doi.org/10.1124/jpet.113.208314
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