DIFFERENCES IN THE PATTERNS OF PHENYTOIN-INDUCED MALFORMATIONS FOLLOWING STIRIPENTOL COADMINISTRATION IN 3 INBRED MOUSE STRAINS

Differences in the patterns of congenital malformations observed in three inbred mouse strains (SWV, LM/Bc, and C57BL/6J) were compared following exposure to phenytoin monotherapy and a polytherapeutic regimen of phenytoin and stiripentol. Treatment groups containing no fewer than 10 dams were chronically exposed to the test compound(s) prior to and throughout gestation. The pattern of fetal defects observed included abnormalities of the neural, cardiac, urogenital, and skeletal systems. The coadministration of the cytochrome P-450-inhibiting antiepileptic drug stiripentol significantly reduced the incidence of fetal malformations in all three strains, primarily by reducing phenytoin's deleterious effects on congenital abnormalities related directly to fetal growth and development. In the SWV fetuses, there were significantly more soft tissue defects (neural and renal) than were evident in the LM/Bc fetuses. Overall, the C57BL/6J fetuses were the most sensitive to the induction of skeletal defects, with a preponderance of defects in the ossification of the craniofacial bones. It is hypothesized that the reduction in fetal defects was the result of limiting the biotransformation of phenytoin to highly teratogenic oxidative metabolites, which interfere with normal fetal growth.