Journal
DRUG METABOLISM AND DISPOSITION
Volume 33, Issue 8, Pages 1158-1165Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.104.002188
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- NIGMS NIH HHS [R01 GM41935, R01 GM041935] Funding Source: Medline
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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 mu mol, 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 similar to 5-fold lower relative to wild-type controls (0.3 +/- 0.1 versus 1.5 +/- 0.3 mu mol). In the presence of GF120918, biliary excretion of AS was decreased similar to 2-fold in both TR- (0.16 +/- 0.09 mu mol) and wild-type (0.8 +/- 0.3 mu mol) rat IPLs. These changes were primarily due to alterations in the rate constant governing biliary excretion of AS, which was decreased similar to 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.
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