title: Multidrug resistance-associated protein 2 is primarily responsible for the biliary excretion of fexofenadine in mice.
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 muM 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 muM) 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 (CL(bile, int)(') = 3.0 ml/h/g liver) could be attributed to Mrp2 (Mrp2-dependent CL(bile, int)(') approximately 1.7 ml/h/g liver), with P-gp and Bcrp playing a minor role (P-gp- and Bcrp-dependent CL(bile, int)(') approximately 0.3 ml/h/g liver). Approximately one third of FEX CL(bile, int)(') 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 CL(bile, int)(') (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.
authors.affiliation: School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Xianbin
authors.initials: X
authors.lastname: Tian
authors.forename: Maciej J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Bridges
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nezasa
authors.forename: Nita J
authors.initials: NJ
authors.lastname: Patel
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Raub
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D039563:Histamine H1 Antagonists, Non-Sedating; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016593:Terfenadine; C093230:fexofenadine