Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1

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 and Kim L. R. Brouwer
Drug Metabolism and Disposition August 2005, 33 (8) 1158-1165; DOI: https://doi.org/10.1124/dmd.104.002188
Maciej J. Zamek-Gliszczynski
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Keith A. Hoffmaster
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xianbin Tian
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rong Zhao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph W. Polli
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joan E. Humphreys
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lindsey O. Webster
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arlene S. Bridges
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Cory Kalvass
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kim L. R. Brouwer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

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

  • 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.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.104.002188.

  • 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
View Full Text

 

DMD articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 33 (8)
Drug Metabolism and Disposition
Vol. 33, Issue 8
1 Aug 2005
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1

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 and Kim L. R. Brouwer
Drug Metabolism and Disposition August 1, 2005, 33 (8) 1158-1165; DOI: https://doi.org/10.1124/dmd.104.002188

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1

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 and Kim L. R. Brouwer
Drug Metabolism and Disposition August 1, 2005, 33 (8) 1158-1165; DOI: https://doi.org/10.1124/dmd.104.002188
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • CYP3A-mediated oxidation of DABE and BIBR0951
  • Adipocyte PXR does not play an essential role in obesity.
  • Biodistribution of Lipid in Rats
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics