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Research ArticleArticle

Peroxidase-Mediated Bioactivation of Hydroxylated Metabolites of Carbamazepine and Phenytoin

Wei Lu and Jack P. Uetrecht
Drug Metabolism and Disposition August 2008, 36 (8) 1624-1636; DOI: https://doi.org/10.1124/dmd.107.019554
Wei Lu
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Jack P. Uetrecht
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Abstract

Carbamazepine (CBZ) and phenytoin (PHN) are associated with a relatively high incidence of idiosyncratic drug reactions. Most such reactions are believed to be due to reactive metabolites. The reactions associated with these two drugs are similar, and if a patient has a reaction to one, he or she is at increased risk of having a reaction to the other, suggesting that a similar reactive metabolite may be involved. CBZ causes neutropenia in approximately 10% of patients; this suggests that reactive metabolites are formed by myeloperoxidase (MPO), the major oxidative enzyme in neutrophils. Major metabolites of CBZ are the 2- and 3-OH metabolites, and that of PHN is the 4-OH metabolite. We found that both 2-OH-CBZ and 3-OH-CBZ were further oxidized by MPO/H2O2, and the oxidation of 3-OH-CBZ was much faster than the oxidation of 2-OH-CBZ or CBZ itself. Oxidation by MPO formed dimers of 3-OH-CBZ and 4-OH-PHN and, in the presence of N-acetyltyrosine, cross dimers were formed. This strongly suggests free radical intermediates. Bioactivation of 3-OH-CBZ and 4-OH-PHN by MPO/H2O2 led to covalent binding to the tyrosine of a model protein. Free radicals usually generate reactive oxygen species (ROS). We also tested the ability of these metabolites to generate ROS and found that 3-OH-CBZ generated more ROS than 2-OH-CBZ, which was, in turn, greater than that generated by CBZ. These results suggest that bioactivation of 3-OH-CBZ and 4-OH-PHN to free radicals by peroxidases may play a role in the ability of these drugs to cause idiosyncratic drug reactions.

Footnotes

  • J.P.U. holds a Canada Research Chair in Adverse Drug Reactions.

  • This work was supported by grants from the Canadian Institutes of Health Research.

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

  • doi:10.1124/dmd.107.019554.

  • ABBREVIATIONS: 2D, two-dimensional; CBZ, carbamazepine; COSY, correlation spectroscopy; 3,4-dihydrodiol, 5-(3′,4′-dihydroxy-1′5′-cyclohexadien-1-yl)-,5-phenylhydantoin; 3,4-diOH-PHN, 5-(3′,4′-dihydroxyphenyl)-,5-phenylhydantoin; ESI, electron spray ionization; HMBC, heteronuclear multiple bond correlation; HPLC, high-performance liquid chromatography; HSQC, heteronuclear single quantum correlation; IDR, idiosyncratic drug reaction; LC, liquid chromatography; MALDI-TOF, matrix-assisted laser desorption/ionization-time of flight; MH+, protonated molecular ion; MPO, myeloperoxidase; MRM, multiple reaction monitoring; MS, mass spectrometry; MS/MS, tandem mass spectrometry; NATyr, N-acetyl tyrosine; NMR, nuclear magnetic resonance; 3-OH-PHN, 3-hydroxyphenytoin; 4-OH-PHN, 4-hydroxyphenytoin; PHN, phenytoin; ROS, reactive oxygen species.

  • ↵1 Current affiliation: Biotransformation, Drug Safety and Metabolism, Wyeth Pharmaceuticals, Collegeville, PA.

    • Received October 31, 2007.
    • Accepted March 6, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (8)
Drug Metabolism and Disposition
Vol. 36, Issue 8
1 Aug 2008
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Research ArticleArticle

Peroxidase-Mediated Bioactivation of Hydroxylated Metabolites of Carbamazepine and Phenytoin

Wei Lu and Jack P. Uetrecht
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1624-1636; DOI: https://doi.org/10.1124/dmd.107.019554

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Research ArticleArticle

Peroxidase-Mediated Bioactivation of Hydroxylated Metabolites of Carbamazepine and Phenytoin

Wei Lu and Jack P. Uetrecht
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1624-1636; DOI: https://doi.org/10.1124/dmd.107.019554
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