Effect of treatment with phenobarbital and stiripentol on carbamazepine-induced teratogenicity and reactive metabolite formation

A model using SWV mice was developed to investigate the mechanistic basis of carbamazepine (CBZ)-related fetotoxicity. Drug administration was initiated prior to conception and continued until day 18 of gestation. The incidence of malformation was 33% following CBZ exposure (1,500 mg/kg/day), compared with a 5% incidence in pair-fed control animals (P < 0.05). Coadministration of nonteratogenic doses of phenobarbital (PB; a cytochrome P-450 inducer) (45 mg/kg/day) and CBZ (1,000 mg/kg/day) increased the frequency of malformation from 10% to 26% (P < 0.05), compared with mice dosed with CBZ alone (1,000 mg/kg/day). Coadministration of stiripentol (STP; a cytochrome P-450 inhibitor) (300 mg/kg/day) decreased the incidence of malformations produced by CBZ (1,500 mg/kg/day) from 33% to 16.7% (P < 0.05). The effect of PB administration on the binding of C-14 in maternal and fetal tissue was assessed in dams that received CBZ (1,000 mg/kg/day) with or without PB (45 mg/kg/day) or STP (300 mg/kg/day) chronically and a single i.p. dose of C-14-CBZ on day 12 of gestation. In all instances, binding was greatest in maternal liver, then in the placenta, fetal head and body, and maternal thigh muscle. In all tissues, PB caused a two- to threefold increase in binding, compared with binding in mice exposed to CBZ alone. STP administration decreased protein adduct formation only in maternal liver. The binding of C-14 was also assessed in hepatic microsomes prepared from female mice exposed to CBZ and PB or STP as in the in vivo study of C-14 binding. The extent of irreversible binding was 67% greater in microsomes prepared from mice pretreated with PB and CBZ than with CBZ alone, while STP resulted in only 21% inhibition of C-14 adduct formation (P < 0.05). The results are consistent with the formation of a chemically reactive teratogenic metabolite of CBZ in mice by cytochrome(s) P-450. (C) 1996 Wiley-Liss, Inc.