Document Detail


Multiple mechanisms are involved in the biliary excretion of acetaminophen sulfate in the rat: role of Mrp2 and Bcrp1.
MedLine Citation:
PMID:  15860656     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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:
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:
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:
Created Date:  2005-07-28     Completed Date:  2006-08-04     Revised Date:  2011-06-21    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1158-65     Citation Subset:  IM    
Affiliation:
School of Pharmacy, CB# 7360, Kerr Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / 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:
R01 GM41935/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
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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