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Molecular Pharmacology

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Research ArticleArticle

Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters

Jurjen S. Lagas, Rolf W. Sparidans, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Molecular Pharmacology April 2010, 77 (4) 687-694; DOI: https://doi.org/10.1124/mol.109.062364
Jurjen S. Lagas
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Rolf W. Sparidans
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Els Wagenaar
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Jos H. Beijnen
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Alfred H. Schinkel
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Abstract

Diclofenac is an important analgesic and anti-inflammatory drug that is widely used for the treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Diclofenac is extensively metabolized in the liver, and the main metabolites are hydroxylated and/or glucuronidated conjugates. We show here that loss of multidrug resistance protein 2 (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) in mice results in highly increased plasma levels of diclofenac acyl glucuronide, after both oral and intravenous administration. The absence of Mrp2 and Bcrp1, localized at the canalicular membrane of hepatocytes, leads to impaired biliary excretion of acyl glucuronides and consequently to elevated liver and plasma levels. Mrp2 also mediates the biliary excretion of two hydroxylated diclofenac metabolites, 4′-hydroxydiclofenac and 5-hydroxydiclofenac. We further show that the sinusoidal efflux of diclofenac acyl glucuronide, from liver to blood, is largely dependent on multidrug resistance protein 3 (MRP3/ABCC3). Diclofenac acyl glucuronides are chemically instable and reactive, and in patients, these metabolites are associated with rare but serious idiosyncratic liver toxicity. This might explain why Mrp2/Mrp3/Bcrp1(−/−) mice, which have markedly elevated levels of diclofenac acyl glucuronides in their liver, display acute, albeit very mild, hepatotoxicity. We believe that the handling of diclofenac acyl glucuronides by ATP binding cassette transporters may be representative for the handling of acyl glucuronide metabolites of many other clinically relevant drugs.

Footnotes

    fn-8
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.062364.

  • fn-9
  • ABBREVIATIONS:

    DF
    diclofenac
    DF-AG
    diclofenac acyl glucuronide
    4OH-DF
    4′-hydroxydiclofenac
    5OH-DF
    5-hydroxydiclofenac
    MRP
    multidrug-resistance protein
    BCRP
    breast cancer resistance protein
    ABC
    ATP binding cassette
    WT
    wild type
    AUC
    area under the plasma concentration-time curve
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    ALAT
    alanine aminotransferase
    UGT
    UDP-glucuronosyltransferase.

    • Received November 12, 2009.
    • Accepted January 19, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters

Jurjen S. Lagas, Rolf W. Sparidans, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Molecular Pharmacology April 1, 2010, 77 (4) 687-694; DOI: https://doi.org/10.1124/mol.109.062364

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Research ArticleArticle

Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters

Jurjen S. Lagas, Rolf W. Sparidans, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Molecular Pharmacology April 1, 2010, 77 (4) 687-694; DOI: https://doi.org/10.1124/mol.109.062364
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