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 Ameri ca; however, its use is associated with a range of serious idiosyncratic ad verse reactions. These reactions are thought to result from the formation o f chemically reactive metabolites. Carbamazepine is extensively metabolized in the liver and one of the major metabolites is 2-hydroxycarbamazepine, w hich has previously been detected as a urinary metabolite excreted by rats and humans along with its further metabolized product, 2-hydroxyiminostilbe ne. 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-hydroxyim inostilbene can be oxidized readily to an iminoquinone species by HOCl, H2O 2 or even on exposure to air. The reactivity of this iminoquinone as an ele ctrophile was studied. It was shown to react with sulfhydryl-containing nuc leophiles, such as glutathione and N-acetylcysteine. We also found a metabo lite with the same molecular weight as C-methylthio-2-hydroxyiminostilbene, but not the corresponding carbamazepine derivative, in the urine of patien ts taking carbamazepine and this presumably reflects the formation of a glu tathione conjugate of the reactive iminoquinone. This iminoquinone intermed iate may play a role in carbamazepine-induced idiosyncratic reactions.