C. Ju et Jp. Uetrecht, Detection of 2-hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate, J PHARM EXP, 288(1), 1999, pp. 51-56
Citations number
31
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.