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First published on May 7, 2008; DOI: 10.1124/dmd.107.019554

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Received for publication November 1, 2007.
Revised February 27, 2008.
Accepted for publication March 6, 2008.

Peroxidase-Mediated Bioactivation of Hydroxylated Metabolites of Carbamazepine and Phenytoin

Wei Lu 1 Jack P Uetrecht 2*

1 Wyeth 2 University of Toronto

* Address correspondence to: E-mail: jack.uetrecht{at}utoronto.ca

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, they are at increased risk of having a reaction to the other suggesting that a similar reactive metabolite may be involved. CBZ causes neutropenia in about 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.


Key words: adverse drug reactions, free radicals, reactive metabolites


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R. E. Pearce, W. Lu, Y. Wang, J. P. Uetrecht, M. A. Correia, and J. S. Leeder
Pathways of Carbamazepine Bioactivation in Vitro. III. The Role of Human Cytochrome P450 Enzymes in the Formation of 2,3-Dihydroxycarbamazepine
Drug Metab. Dispos., August 1, 2008; 36(8): 1637 - 1649.
[Abstract] [Full Text] [PDF]


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