RT Journal Article
SR Electronic
T1 Multidrug Resistance-Associated Protein 2 Is Primarily Responsible for the Biliary Excretion of Fexofenadine in Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 61
OP 64
DO 10.1124/dmd.107.017319
VO 36
IS 1
A1 Tian, Xianbin
A1 Zamek-Gliszczynski, Maciej J.
A1 Li, Jun
A1 Bridges, Arlene S.
A1 Nezasa, Ken-ichi
A1 Patel, Nita J.
A1 Raub, Thomas J.
A1 Brouwer, Kim L. R.
YR 2008
UL http://dmd.aspetjournals.org/content/36/1/61.abstract
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