Abstract
The hepatic excretion of hydrophilic conjugates, end products of phase II metabolism, is not completely understood. In the present studies, transport mechanism(s) responsible for the biliary excretion of 4-methylumbelliferyl glucuronide (4MUG) and 4-methylumbelliferyl sulfate (4MUS) were studied. Isolated perfused livers (IPLs) from Mrp2-deficient (TR-) Wistar rats were used to examine the role of Mrp2 in the biliary excretion of 4MUG and 4MUS. After a 30-μmol dose of 4-methylumbelliferone, cumulative biliary excretion of 4MUG was extensive in wild-type rat IPLs (25 ± 3 μmol) but was negligible in TR- livers (0.4 ± 0.1 μmol); coadministration of the Bcrp 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] had no effect on 4MUG biliary excretion in wild-type rat IPLs. In contrast, biliary excretion of 4MUS was partially maintained in Mrp2-deficient rat IPLs. Recovery of 4MUS in bile was ∼50 to 60% lower in both control TR- (149 ± 8 nmol) and wild-type IPLs with GF120918 coadministration (176 ± 30 nmol) relative to wild-type control livers (378 ± 37 nmol) and was nearly abolished in TR- IPLs in the presence of GF120918 (13 ± 8 nmol). These changes were the result of decreased rate constants governing 4MUG and 4MUS biliary excretion. In vitro assays and perfused livers from Bcrp and P-glycoprotein gene-knockout mice indicated that 4MUS did not interact with P-glycoprotein but was transported by Bcrp in a GF120918-sensitive manner. In the rat liver, Mrp2 mediates the biliary excretion of 4MUG, whereas both Mrp2 and Bcrp contribute almost equally to the transport of 4MUS into bile.
Footnotes
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This work was funded by Grant R01 GM41935 from the National Institutes of Health.
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Supported by an Eli Lilly and Company Foundation Predoctoral Fellowship in Pharmacokinetics and Drug Disposition. Findings were presented in part at the 2005 American Association of Pharmaceutical Scientists (AAPS); 2005 Nov 6-10; Nashville, TN. AAPS, Arlington, VA.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.101840.
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ABBREVIATIONS: Mrp, Abcc, multidrug resistance-associated protein; Mdr, multidrug resistance; 4MUG, 4-methylumbelliferyl glucuronide; 4MUS, 4-methylumbelliferyl sulfate; Bcrp, Abcg2, breast cancer resistance protein; IPL, isolated perfused liver; MDCKII, Madin-Darby canine kidney II; 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; PAMPA, parallel artificial membrane permeability assay; TR-, Mrp2-deficient; UGT, uridine diphosphate-glucuronosyl transferase; SN-38, 7-ethyl-10-hydroxycamptothecin; AM, acetoxymethyl ester.
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↵1 Current affiliation: Eli Lilly & Co., Drug Disposition, Indianapolis, Indiana.
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↵2 Current affiliation: Shionogi & Co., Ltd., Developmental Research Laboratories, Toyonaka, Osaka, Japan.
- Received January 25, 2006.
- Accepted July 18, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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