Received for publication June 21, 2007.
Revised September 28, 2007.
Accepted for publication October 1, 2007.

Multidrug Resistance-Associated Protein 2 (Mrp2) is Primarily Responsible for the Biliary Excretion of Fexofenadine (FEX) 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 Bcrp-knockout mice, and 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. 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 vs. 122 ± 34 pmol/min/g liver). In mice, more than 50% of FEX unbound intrinsic biliary clearance (CL_{bile, int} = 3.0 ml/hr/g liver) could be attributed to Mrp2 (Mrp2-dependent CL_{bile, int} ~ 1.7 ml/hr/g liver), with P-gp and Bcrp playing a minor role (P-gp- and Bcrp-dependent CL_{bile, int} ~ 0.3 ml/hr/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 ± 2.5 and 6.49 ± 0.68 ml/hr/g liver) were comparable between Mrp2-deficient (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.

Key words: ABC transporters, biliary excretion, drug transport, hepatic elimination, hepatic transport, hepatic uptake, hepatobiliary disposition, hepatobiliary transport