PT - JOURNAL ARTICLE AU - Maciej J. Zamek-Gliszczynski AU - Keith A. Hoffmaster AU - Xianbin Tian AU - Rong Zhao AU - Joseph W. Polli AU - Joan E. Humphreys AU - Lindsey O. Webster AU - Arlene S. Bridges AU - J. Cory Kalvass AU - Kim L. R. Brouwer TI - MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1 AID - 10.1124/dmd.104.002188 DP - 2005 Aug 01 TA - Drug Metabolism and Disposition PG - 1158--1165 VI - 33 IP - 8 4099 - http://dmd.aspetjournals.org/content/33/8/1158.short 4100 - http://dmd.aspetjournals.org/content/33/8/1158.full SO - Drug Metab Dispos2005 Aug 01; 33 AB - Previous reports have demonstrated that sulfate metabolites may be excreted into bile by the multidrug resistance-associated protein 2 (Mrp2, Abcc2). Although recombinant human breast cancer resistance protein (BCRP, ABCG2) has affinity for sulfated xenobiotics and endobiotics, its relative importance in biliary excretion of sulfate metabolites in the intact liver is unknown. In the present studies, the potential contribution of Bcrp1 to the biliary excretion of acetaminophen sulfate (AS) was examined following acetaminophen administration (66 μmol, bolus) to isolated perfused livers (IPLs) from wild-type Wistar and Mrp2-deficient (TR-) Wistar rats in the presence or absence of the Bcrp1 and P-glycoprotein inhibitor, 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]. Recovery of AS in bile of TR- rat livers was ∼5-fold lower relative to wild-type controls (0.3 ± 0.1 versus 1.5 ± 0.3 μmol). In the presence of GF120918, biliary excretion of AS was decreased ∼2-fold in both TR- (0.16 ± 0.09 μmol) and wild-type (0.8 ± 0.3 μmol) rat IPLs. These changes were primarily due to alterations in the rate constant governing biliary excretion of AS, which was decreased ∼90% in TR- relative to wild-type rat IPLs (0.02 ± 0.01 versus 0.2 ± 0.1 h-1) and was further decreased in the presence of GF120918 (0.010 ± 0.003 and 0.12 ± 0.05 h-1; TR- and wild-type, respectively). In vitro assays indicated that impaired AS biliary excretion in the presence of GF120918 was due to inhibition of Bcrp1, and not P-glycoprotein. In conclusion, Mrp2 and, to a lesser extent, Bcrp1 mediate biliary excretion of AS in the intact liver. The American Society for Pharmacology and Experimental Therapeutics