Effects of pretreatment with SKF-525A or sodium phenobarbital on thiabendazole-induced teratogenicity in ICR mice.

To study the effects of SKF-525A, an inhibitor of cytochrome P-450, and of sodium phenobarbital (PB), a drug-metabolizing enzyme inducer, on the teratogenicity of thiabendazole (TBZ), pregnant mice were given ip either a single dose of 40 mg SKF-525A/kg 1 hr before oral dosing with 250 or 500 mg TBZ/kg or a dose of 75 mg PB/kg/day on three consecutive days before oral administration of a dose of 500 or 1000 mg TBZ/kg. In either case the TBZ dose was given on day 9 of gestation. All foetuses were removed from the uterus on day 18 of gestation, and were examined for external and skeletal anomalies. The spectrum of malformations in the groups of mice pretreated with SKF-525A or PB was similar to that in mice treated only with TBZ. In the group pretreated with SKF-525A, however, the incidence of resorbed foetuses was higher than in the group treated with TBZ alone and there was a tendency towards an increase in the number of foetuses with skeletal fusion and reduction deformity of the limbs, an anomaly characteristically induced by TBZ. On the other hand, in mice pretreated with PB, the incidence of resorbed foetuses tended to be lower, the numbers and body weights of live foetuses were higher and the incidence of external and skeletal malformations was lower than in the groups treated with TBZ only. No reduction deformity of the limbs was observed in the groups pretreated with PB. These results suggest that with TBZ the ultimate teratogen may be the parent compound rather than its metabolites.