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Research ArticleArticle

Multidrug Resistance-Associated Protein 2 Is Primarily Responsible for the Biliary Excretion of Fexofenadine in Mice

Xianbin Tian, Maciej J. Zamek-Gliszczynski, Jun Li, Arlene S. Bridges, Ken-ichi Nezasa, Nita J. Patel, Thomas J. Raub and Kim L. R. Brouwer
Drug Metabolism and Disposition January 2008, 36 (1) 61-64; DOI: https://doi.org/10.1124/dmd.107.017319
Xianbin Tian
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Maciej J. Zamek-Gliszczynski
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Jun Li
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Arlene S. Bridges
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Ken-ichi Nezasa
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Nita J. Patel
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Thomas J. Raub
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Kim L. R. Brouwer
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Abstract

Previous studies implicated P-glycoprotein (P-gp) as the major transport protein responsible for the biliary excretion of fexofenadine (FEX). However, FEX biliary excretion was not impaired in P-gp- or breast cancer resistance protein (Bcrp)-knockout mice or multidrug resistance-associated protein 2 (Mrp2)-deficient rats. The present study tested the hypothesis that species differences exist in the transport protein primarily responsible for FEX biliary excretion between mice and rats. Livers from Mrp2-knockout (Mrp2KO) mice and Mrp2-deficient (TR-) rats were perfused in a single-pass manner with 0.5 μM FEX. N-(4-[2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (10 μM) was employed to inhibit P-gp and Bcrp. The biliary excretion rate of FEX was decreased 85% in Mrp2KO relative to wild-type mice (18.4 ± 2.2 versus 122 ± 34 pmol/min/g liver). In mice, more than 50% of FEX unbound intrinsic biliary clearance (Math = 3.0 ml/h/g liver) could be attributed to Mrp2 (Mrp2-dependent Math ∼ 1.7 ml/h/g liver), with P-gp and Bcrp playing a minor role (P-gp- and Bcrp-dependent Math ∼ 0.3 ml/h/g liver). Approximately one third of FEX Math was attributed to unidentified mechanisms in mice. In contrast to mice, FEX biliary excretion rate (245 ± 38 and 250 ± 25 pmol/min/g liver) and Math (9.72 ± 2.47 and 6.49 ± 0.68 ml/h/g liver) were comparable between TR- and control Wistar rats, respectively, suggesting that unidentified transport mechanism(s) can completely compensate for the loss of Mrp2 function in rats. Mrp2 clearly plays a major role in FEX biliary excretion in mice. In conclusion, remarkable species differences exist in FEX hepatobiliary transport mechanisms.

Footnotes

  • This work was supported by National Institutes of Health Grant R01 GM41935 and Eli Lilly and Company.

  • Current affiliations: Wyeth, Discovery Pharmacokinetics, Andover, Massachusetts (X.T.); Eli Lilly and Company, Drug Disposition, Indianapolis, Indiana (M.J.Z-G.); Shionogi & Co., Ltd., Developmental Research Laboratories, Osaka, Japan (K.N.).

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

  • doi:10.1124/dmd.107.017319.

  • ABBREVIATIONS: FEX, fexofenadine; Bcrp, breast cancer resistance protein; B6, wild-type C57BL/6 mouse; Math, unbound intrinsic biliary clearance; Cliver, total liver concentration; Cliver, unbound, unbound liver concentration; Css, out, outflow perfusate concentration at steady state; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; Mrp2, multidrug resistance-associated protein 2; Mrp2KO, Mrp2-knockout; Oatp, organic anion transporting polypeptide; P-gp, P-glycoprotein; TR-, Mrp2-deficient Wistar rat.

    • Received June 20, 2007.
    • Accepted October 1, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (1)
Drug Metabolism and Disposition
Vol. 36, Issue 1
1 Jan 2008
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Research ArticleArticle

Multidrug Resistance-Associated Protein 2 Is Primarily Responsible for the Biliary Excretion of Fexofenadine in Mice

Xianbin Tian, Maciej J. Zamek-Gliszczynski, Jun Li, Arlene S. Bridges, Ken-ichi Nezasa, Nita J. Patel, Thomas J. Raub and Kim L. R. Brouwer
Drug Metabolism and Disposition January 1, 2008, 36 (1) 61-64; DOI: https://doi.org/10.1124/dmd.107.017319

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Research ArticleArticle

Multidrug Resistance-Associated Protein 2 Is Primarily Responsible for the Biliary Excretion of Fexofenadine in Mice

Xianbin Tian, Maciej J. Zamek-Gliszczynski, Jun Li, Arlene S. Bridges, Ken-ichi Nezasa, Nita J. Patel, Thomas J. Raub and Kim L. R. Brouwer
Drug Metabolism and Disposition January 1, 2008, 36 (1) 61-64; DOI: https://doi.org/10.1124/dmd.107.017319
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