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Research ArticleArticle

EVIDENCE FOR THE BIOACTIVATION OF ZOMEPIRAC AND TOLMETIN BY AN OXIDATIVE PATHWAY: IDENTIFICATION OF GLUTATHIONE ADDUCTS IN VITRO IN HUMAN LIVER MICROSOMES AND IN VIVO IN RATS

Qing Chen, George A. Doss, Elaine C. Tung, Wensheng Liu, Yui S. Tang, Matthew P. Braun, Varsha Didolkar, John R. Strauss, Regina W. Wang, Ralph A. Stearns, David C. Evans, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition January 2006, 34 (1) 145-151; DOI: https://doi.org/10.1124/dmd.105.004341
Qing Chen
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George A. Doss
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Elaine C. Tung
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Wensheng Liu
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Yui S. Tang
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Matthew P. Braun
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Varsha Didolkar
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John R. Strauss
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Regina W. Wang
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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

Although zomepirac (ZP) and tolmetin (TM) induce anaphylactic reactions and form reactive acyl glucuronides, a direct link between the two events remains obscure. We report herein that, in addition to acyl glucuronidation, both drugs are subject to oxidative bioactivation. Following incubations of ZP with human liver microsomes fortified with NADPH and glutathione (GSH), a metabolite with an MH+ ion at m/z 597 was detected by LC/MS/MS. On the basis of collision-induced dissociation and NMR evidence, the structure of this metabolite was determined to be 5-[4′-chlorobenzoyl]-1,4-dimethyl-3-glutathionylpyrrole-2-acetic acid (ZP-SG), suggesting that the pyrrole moiety of ZP had undergone oxidation to an epoxide intermediate, followed by addition of GSH and loss of the elements of H2O to yield the observed conjugate. The oxidative bioactivation of ZP most likely is catalyzed by cytochrome P450 (P450) 3A4, since the formation of ZP-SG was reduced to ∼10% of control values following pretreatment of human liver microsomes with ketoconazole or with an inhibitory anti-P450 3A4 IgG. A similar GSH adduct, namely 5-[4′-methylbenzoyl]-1-methyl-3-glutathionylpyrrole-2-acetic acid (TM-SG), was identified when TM was incubated with human liver microsomal preparations. The relevance of these in vitro findings to the in vivo situation was established through the detection of the same thiol adducts in rats treated with ZP and TM, respectively. Taken together, these data suggest that, in addition to the formation of acyl glucuronides, oxidative metabolism of ZP and TM affords reactive species that may haptenize proteins and thereby contribute to the drug-mediated anaphylactic reactions.

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

  • doi:10.1124/dmd.105.004341.

  • ABBREVIATIONS: GSH, reduced glutathione; ZP, zomepirac; TM, tolmetin; NSAID, nonsteroidal anti-inflammatory drug; P450, cytochrome P450; LC/MS/MS, liquid chromatography-tandem mass spectrometry; HPLC, high-performance liquid chromatography; CID, collision-induced dissociation; SRM, selected reaction monitoring; ZP-SG, 5-[4′-chlorobenzoyl]-1,4-dimethyl-3-glutathionylpyrrole-2-acetic acid; TM-SG, 5-[4′-methylbenzoyl]-1-methyl-3-glutathionylpyrrole-2-acetic acid.

    • Received February 18, 2005.
    • Accepted October 19, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (1)
Drug Metabolism and Disposition
Vol. 34, Issue 1
1 Jan 2006
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EVIDENCE FOR THE BIOACTIVATION OF ZOMEPIRAC AND TOLMETIN BY AN OXIDATIVE PATHWAY: IDENTIFICATION OF GLUTATHIONE ADDUCTS IN VITRO IN HUMAN LIVER MICROSOMES AND IN VIVO IN RATS
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Research ArticleArticle

EVIDENCE FOR THE BIOACTIVATION OF ZOMEPIRAC AND TOLMETIN BY AN OXIDATIVE PATHWAY: IDENTIFICATION OF GLUTATHIONE ADDUCTS IN VITRO IN HUMAN LIVER MICROSOMES AND IN VIVO IN RATS

Qing Chen, George A. Doss, Elaine C. Tung, Wensheng Liu, Yui S. Tang, Matthew P. Braun, Varsha Didolkar, John R. Strauss, Regina W. Wang, Ralph A. Stearns, David C. Evans, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition January 1, 2006, 34 (1) 145-151; DOI: https://doi.org/10.1124/dmd.105.004341

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Research ArticleArticle

EVIDENCE FOR THE BIOACTIVATION OF ZOMEPIRAC AND TOLMETIN BY AN OXIDATIVE PATHWAY: IDENTIFICATION OF GLUTATHIONE ADDUCTS IN VITRO IN HUMAN LIVER MICROSOMES AND IN VIVO IN RATS

Qing Chen, George A. Doss, Elaine C. Tung, Wensheng Liu, Yui S. Tang, Matthew P. Braun, Varsha Didolkar, John R. Strauss, Regina W. Wang, Ralph A. Stearns, David C. Evans, Thomas A. Baillie and Wei Tang
Drug Metabolism and Disposition January 1, 2006, 34 (1) 145-151; DOI: https://doi.org/10.1124/dmd.105.004341
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