These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Peroxidase-mediated bioactivation of hydroxylated metabolites of carbamazepine and phenytoin.
    Author: Lu W, Uetrecht JP.
    Journal: Drug Metab Dispos; 2008 Aug; 36(8):1624-36. PubMed ID: 18463199.
    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.
    [Abstract] [Full Text] [Related] [New Search]