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Research ArticleArticle

Characterization of Niflumic Acid as a Selective Inhibitor of Human Liver Microsomal UDP-Glucuronosyltransferase 1A9: Application to the Reaction Phenotyping of Acetaminophen Glucuronidation

John O. Miners, Kushari Bowalgaha, David J. Elliot, Pawel Baranczewski and Kathleen M. Knights
Drug Metabolism and Disposition April 2011, 39 (4) 644-652; DOI: https://doi.org/10.1124/dmd.110.037036
John O. Miners
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Kushari Bowalgaha
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David J. Elliot
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Pawel Baranczewski
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Kathleen M. Knights
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Enzyme selective inhibitors represent the most valuable experimental tool for reaction phenotyping. However, only a limited number of UDP-glucuronosyltransferase (UGT) enzyme-selective inhibitors have been identified to date. This study characterized the UGT enzyme selectivity of niflumic acid (NFA). It was demonstrated that 2.5 μM NFA is a highly selective inhibitor of recombinant and human liver microsomal UGT1A9 activity. Higher NFA concentrations (50–100 μM) inhibited UGT1A1 and UGT2B15 but had little effect on the activities of UGT1A3, UGT1A4, UGT1A6, UGT2B4, UGT2B7, and UGT2B17. NFA inhibited 4-methylumbelliferone and propofol (PRO) glucuronidation by recombinant UGT1A9 and PRO glucuronidation by human liver microsomes (HLM) according to a mixed (competitive-noncompetitive) mechanism, with Ki values ranging from 0.10 to 0.40 μM. Likewise, NFA was a mixed or noncompetitive inhibitor of recombinant and human liver microsomal UGT1A1 (Ki range 14–18 μM), whereas competitive inhibition (Ki 62 μM) was observed with UGT2B15. NFA was subsequently applied to the reaction phenotyping of human liver microsomal acetaminophen (APAP) glucuronidation. Consistent with previous reports, APAP was glucuronidated by recombinant UGT1A1, UGT1A6, UGT1A9, and UGT2B15. NFA concentrations in the range of 2.5 to 100 μM inhibited APAP glucuronidation by UGT1A1, UGT1A9, and UGT2B15 but not by UGT1A6. The mean Vmax for APAP glucuronidation by HLM was reduced by 20, 35, and 40%, respectively, in the presence of 2.5, 50, and 100 μM NFA. Mean Km values decreased in parallel with Vmax, although the magnitude of the decrease was smaller. Taken together, the NFA inhibition data suggest that UGT1A6 is the major enzyme involved in APAP glucuronidation.

Footnotes

  • This work was supported by the National Health and Medical Research Council of Australia.

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

    doi:10.1124/dmd.110.037036.

  • ABBREVIATIONS:

    UGT
    UDP-glucuronosyltransferase
    HLM
    human liver microsomes
    NFA
    niflumic acid
    APAP
    acetaminophen (N-acetyl-p-aminophenol)
    APAPG
    acetaminophen β-d-glucuronide
    COD
    codeine
    4MU
    4-methylumbelliferone
    β-E2
    β-estradiol
    PRO
    propofol
    TST
    testosterone
    TFP
    trifluoperazine
    UDPGA
    UDP-glucuronic acid
    AZT
    zidovudine
    DEFG
    deferiprone 3-O-β-d-glucuronide
    LTG
    lamotrigine
    DEF
    deferiprone
    HPLC
    high-performance liquid chromatography
    EI
    enzyme-inhibitor
    ESI
    enzyme-inhibitor substrate
    HEK
    human embryonic.

  • Received November 3, 2010.
  • Accepted January 18, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (4)
Drug Metabolism and Disposition
Vol. 39, Issue 4
1 Apr 2011
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Research ArticleArticle

Characterization of Niflumic Acid as a Selective Inhibitor of Human Liver Microsomal UDP-Glucuronosyltransferase 1A9: Application to the Reaction Phenotyping of Acetaminophen Glucuronidation

John O. Miners, Kushari Bowalgaha, David J. Elliot, Pawel Baranczewski and Kathleen M. Knights
Drug Metabolism and Disposition April 1, 2011, 39 (4) 644-652; DOI: https://doi.org/10.1124/dmd.110.037036

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Research ArticleArticle

Characterization of Niflumic Acid as a Selective Inhibitor of Human Liver Microsomal UDP-Glucuronosyltransferase 1A9: Application to the Reaction Phenotyping of Acetaminophen Glucuronidation

John O. Miners, Kushari Bowalgaha, David J. Elliot, Pawel Baranczewski and Kathleen M. Knights
Drug Metabolism and Disposition April 1, 2011, 39 (4) 644-652; DOI: https://doi.org/10.1124/dmd.110.037036
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