Detection of 2-hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate.
Carbamazepine is one of the most widely used anticonvulsants in North America; however, its use is associated with a range of serious idiosyncratic adverse reactions. These reactions are thought to result from the formation of chemically reactive metabolites. Carbamazepine is extensively metabolized in the liver and one of the major metabolites is 2-hydroxycarbamazepine, which has previously been detected as a urinary metabolite excreted by rats and humans along with its further metabolized product, 2-hydroxyiminostilbene. In this study, we found that the urine of patients taking carbamazepine appeared to contain more of the glucuronide of 2-hydroxyiminostilbene than that of 2-hydroxycarbamazepine. We have also demonstrated that 2-hydroxyiminostilbene can be oxidized readily to an iminoquinone species by HOCl, H2O2 or even on exposure to air. The reactivity of this iminoquinone as an electrophile was studied. It was shown to react with sulfhydryl-containing nucleophiles, such as glutathione and N-acetylcysteine. We also found a metabolite with the same molecular weight as 4-methylthio-2-hydroxyiminostilbene, but not the corresponding carbamazepine derivative, in the urine of patients taking carbamazepine and this presumably reflects the formation of a glutathione conjugate of the reactive iminoquinone. This iminoquinone intermediate may play a role in carbamazepine-induced idiosyncratic reactions.
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Faculty of Pharmacy, University of Toronto, Toronto, Canada.
Uetrecht
J P
JP
D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000378:metabolism* / Q000493:pharmacokinetics; D002220:Carbamazepine / Q000378:metabolism* / Q000493:pharmacokinetics; D003984:Dibenzazepines / Q000652:urine*; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism*
C116898:2-hydroxyiminostilbene; D000927:Anticonvulsants; D003984:Dibenzazepines; D011809:Quinones; C116897:iminoquinone; D002220:Carbamazepine