Abstract
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.
Footnotes
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This work was funded by Grant R01 GM41935 from the National Institutes of Health. M.J. Z.-G. was supported by an Eli Lilly and Company Foundation Predoctoral Fellowship in Pharmacokinetics and Drug Disposition.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002188.
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ABBREVIATIONS: E3040, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole; AS, acetaminophen sulfate; AUC, area under the concentration curve; Bcrp1 (Abcg2), breast cancer resistance protein 1; 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; IPL, isolated perfused liver; MDCKII, Madin-Darby canine kidney II; Mrp2 (Abcc2), multidrug resistance-associated protein 2; Mrp3 (Abcc3), multidrug resistance-associated protein 3; Mdr1 (Abcb1), multidrug resistance protein 1, P-glycoprotein.
- Received September 3, 2004.
- Accepted April 27, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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