CHARACTERIZATION OF CARBAMAZEPINE METABOLISM IN A MOUSE MODEL OF CARBAMAZEPINE TERATOGENICITY

The disposition of carbamazepine (CBZ) was investigated in the SWV mou se, A C-14-CBZ dose was administered to CBZ pretreated mice, and the d istribution of radiolabeled material was determined, Twenty-four hours after the C-14-CBZ dose, 92.5% of the dose was accounted for in urine (56%), in the visera and carcass (22%), in feces (11%), and expired a s (CO2)-C-14 (2%). CBZ metabolites present in hydrolyzed urine were al so identified using a combination of spectroscopic techniques, CBZ, CB Z-10,11-epoxide (CBZE), 2- and 3-hydroxy-CBZ, methylsulfonyl-CBZ, and glucuronides of CBZ and CBZE accounted for 64% of total urinary radioa ctivity (0-24 hr) in CBZ pretreated mice, Minor metabolites of CBZ inc luded novel cysteine and N-acetylcysteine conjugates of CBZ, as well a s a methylsulfonyl conjugate of CBZE not previously reported. The urin ary excretion of these thioether conjugates was increased in CBZ/pheno barbital pretreated mice and decreased in CBZ/stiripentol pretreated m ice in comparison with CBZ-only treated mice, Preliminary studies of t he effects of phenobarbital and stiripentol on the urinary abundance o f these metabolites are consistent with the modulation of teratogenici ty in the SWV mouse by the same pretreatments, These data suggest the formation of thioether metabolites of CBZ may be related to CBZ terato genicity in the SWV mouse.