| Multiple mechanisms are involved in the biliary excretion of acetaminophen sulfate in the rat: role of Mrp2 and Bcrp1. | |
MedLine Citation:
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PMID: 15860656 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 micromol, 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 approximately 5-fold lower relative to wild-type controls (0.3 +/- 0.1 versus 1.5 +/- 0.3 micromol). In the presence of GF120918, biliary excretion of AS was decreased approximately 2-fold in both TR(-) (0.16 +/- 0.09 micromol) and wild-type (0.8 +/- 0.3 micromol) rat IPLs. These changes were primarily due to alterations in the rate constant governing biliary excretion of AS, which was decreased approximately 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. |
Authors:
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Maciej J Zamek-Gliszczynski; Keith A Hoffmaster; Xianbin Tian; Rong Zhao; Joseph W Polli; Joan E Humphreys; Lindsey O Webster; Arlene S Bridges; J Cory Kalvass; Kim L R Brouwer |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2005-04-28 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 33 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2005 Aug |
Date Detail:
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Created Date: 2005-07-28 Completed Date: 2006-08-04 Revised Date: 2011-06-21 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 1158-65 Citation Subset: IM |
Affiliation:
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School of Pharmacy, CB# 7360, Kerr Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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antagonists & inhibitors,
metabolism* Acetaminophen / analogs & derivatives*, metabolism, pharmacology* Acridines / pharmacology Animals Bile / chemistry, drug effects, metabolism* Kinetics Liver / drug effects, metabolism* Male Membrane Transport Proteins / deficiency, genetics, metabolism* Multidrug Resistance-Associated Proteins / deficiency, genetics, metabolism* P-Glycoprotein / antagonists & inhibitors Perfusion Rats Rats, Wistar Tetrahydroisoquinolines / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM41935/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATP-Binding Cassette Transporters; 0/Abcg2 protein, rat; 0/Acridines; 0/Membrane Transport Proteins; 0/Multidrug Resistance-Associated Proteins; 0/P-Glycoprotein; 0/Tetrahydroisoquinolines; 0/multidrug resistance-associated protein 2; 10066-90-7/acetaminophen sulfate ester; 103-90-2/Acetaminophen; 143664-11-3/GF 120918 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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