PT  - JOURNAL ARTICLE
AU  - Xianbin Tian
AU  - Maciej J. Zamek-Gliszczynski
AU  - Jun Li
AU  - Arlene S. Bridges
AU  - Ken-ichi Nezasa
AU  - Nita J. Patel
AU  - Thomas J. Raub
AU  - Kim L. R. Brouwer
TI  - Multidrug Resistance-Associated Protein 2 Is Primarily Responsible for the Biliary Excretion of Fexofenadine in Mice
AID  - 10.1124/dmd.107.017319
DP  - 2008 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 61--64
VI  - 36
IP  - 1
4099  - http://dmd.aspetjournals.org/content/36/1/61.short
4100  - http://dmd.aspetjournals.org/content/36/1/61.full
SO  - Drug Metab Dispos2008 Jan 01; 36
AB  - 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 (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{CL}_{\mathrm{bile},{\ }\mathrm{int}}^{{^\prime}}\) \end{document} = 3.0 ml/h/g liver) could be attributed to Mrp2 (Mrp2-dependent \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{CL}_{\mathrm{bile},{\ }\mathrm{int}}^{{^\prime}}\) \end{document} ∼ 1.7 ml/h/g liver), with P-gp and Bcrp playing a minor role (P-gp- and Bcrp-dependent \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{CL}_{\mathrm{bile},{\ }\mathrm{int}}^{{^\prime}}\) \end{document} ∼ 0.3 ml/h/g liver). Approximately one third of FEX \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{CL}_{\mathrm{bile},{\ }\mathrm{int}}^{{^\prime}}\) \end{document} 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 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{CL}_{\mathrm{bile},{\ }\mathrm{int}}^{{^\prime}}\) \end{document} (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. The American Society for Pharmacology and Experimental Therapeutics