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Research ArticleArticle

Bioactivation of Diclofenac via Benzoquinone Imine Intermediates—Identification of Urinary Mercapturic Acid Derivatives in Rats and Humans

Grace K. Poon, Qing Chen, Yohannes Teffera, Jason S. Ngui, Patrick R. Griffin, Mathew P. Braun, George A. Doss, Christopher Freeden, Ralph A. Stearns, David C. Evans, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition December 2001, 29 (12) 1608-1613;
Grace K. Poon
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Qing Chen
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Yohannes Teffera
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Jason S. Ngui
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Patrick R. Griffin
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Mathew P. Braun
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George A. Doss
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Christopher Freeden
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Ralph A. Stearns
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David C. Evans
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Thomas A. Baillie
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Wei Tang
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Abstract

The metabolism of diclofenac has been reported to produce reactive benzoquinone imine intermediates. We describe the identification of mercapturic acid derivatives of diclofenac in rats and humans. Three male Sprague-Dawley rats were administered diclofenac in aqueous solution (pH 7) at 50 mg/kg by intraperitoneal injection, and urine was collected for 24 h. Human urine specimens were obtained, and samples were pooled from 50 individuals. Urine samples were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Two metabolites with MH+ ions atm/z 473 were detected in rat urine and identified tentatively as N-acetylcysteine conjugates of monohydroxydiclofenac. Based upon collision-induced fragmentation of the MH+ ions, accurate mass measurements of product ions, and comparison of LC/MS/MS properties of the metabolites with those of synthetic reference compounds, one metabolite was assigned as 5-hydroxy-4-(N-acetylcystein-S-yl)diclofenac and the other as 4′-hydroxy-3′-(N-acetylcystein-S-yl)diclofenac. The former conjugate also was detected in the pooled human urine sample by multiple reaction-monitoring LC/MS/MS analysis. It is likely that these mercapturic acid derivatives represent degradation products of the corresponding glutathione adducts derived from diclofenac-2,5-quinone imine and 1′,4′-quinone imine, respectively. Our data are consistent with previous findings, which suggest that oxidative bioactivation of diclofenac in humans proceeds via benzoquinone imine intermediates.

Footnotes

  • Abbreviations used are::
    CYP
    cytochrome P450
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    HPLC
    high-pressure liquid chromatography
    CID
    collision-induced dissociation
    5-OH-4-NAC-diclofenac (M1)
    5-hydroxy-4-(N-acetylcystein-S-yl)diclofenac
    4′-OH-3′-NAC-diclofenac (M2)
    4′-hydroxy- 3′-(N-acetylcystein-S-yl)diclofenac
    • Received July 9, 2001.
    • Accepted September 14, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (12)
Drug Metabolism and Disposition
Vol. 29, Issue 12
1 Dec 2001
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Research ArticleArticle

Bioactivation of Diclofenac via Benzoquinone Imine Intermediates—Identification of Urinary Mercapturic Acid Derivatives in Rats and Humans

Grace K. Poon, Qing Chen, Yohannes Teffera, Jason S. Ngui, Patrick R. Griffin, Mathew P. Braun, George A. Doss, Christopher Freeden, Ralph A. Stearns, David C. Evans, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1608-1613;

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Research ArticleArticle

Bioactivation of Diclofenac via Benzoquinone Imine Intermediates—Identification of Urinary Mercapturic Acid Derivatives in Rats and Humans

Grace K. Poon, Qing Chen, Yohannes Teffera, Jason S. Ngui, Patrick R. Griffin, Mathew P. Braun, George A. Doss, Christopher Freeden, Ralph A. Stearns, David C. Evans, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1608-1613;
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