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Departments of
Pharmaceutics (B.M.A., T.F.K., J.T.S.) and
Medicinal
Chemistry (G.L.S., A.P.H., S.D.N.), School of Pharmacy, University of
Washington; and
Department of Veterinary Anatomy and Public Health
(G.D.B., R.H.F.), Texas A & M University
The disposition of carbamazepine (CBZ) was investigated in the SWV
mouse. A 14C-CBZ dose was administered to CBZ pretreated
mice, and the distribution of radiolabeled material was determined.
Twenty-four hours after the 14C-CBZ dose, 92.5% of the
dose was accounted for in urine (56%), in the visera and carcass
(22%), in feces (11%), and expired as 14CO2
(2%). CBZ metabolites present in hydrolyzed urine were also identified
using a combination of spectroscopic techniques. CBZ, CBZ-10,11-epoxide
(CBZE), 2- and 3-hydroxy-CBZ, methylsulfonyl-CBZ, and glucuronides of
CBZ and CBZE accounted for 64% of total urinary radioactivity (0-24
hr) in CBZ pretreated mice. Minor metabolites of CBZ included novel
cysteine and N-acetylcysteine conjugates of CBZ, as well as
a methylsulfonyl conjugate of CBZE not previously reported. The urinary
excretion of these thioether conjugates was increased in
CBZ/phenobarbital pretreated mice and decreased in CBZ/stiripentol
pretreated mice in comparison with CBZ-only treated mice. Preliminary
studies of the effects of phenobarbital and stiripentol on the urinary
abundance of these metabolites are consistent with the modulation of
teratogenicity in the SWV mouse by the same pretreatments. These data
suggest the formation of thioether metabolites of CBZ may be related to
CBZ teratogenicity in the SWV mouse.
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