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 th ree inbred mouse strains (SWV, LM/Bc, and C57BL/6J) were compared foll owing exposure to phenytoin monotherapy and a polytherapeutic regimen of phenytoin and stiripentol. Treatment groups containing no fewer tha n 10 dams were chronically exposed to the test compound(s) prior to an d throughout gestation. The pattern of fetal defects observed included abnormalities of the neural, cardiac, urogenital, and skeletal system s. The coadministration of the cytochrome P-450-inhibiting antiepilept ic drug stiripentol significantly reduced the incidence of fetal malfo rmations in all three strains, primarily by reducing phenytoin's delet erious effects on congenital abnormalities related directly to fetal g rowth and development. In the SWV fetuses, there were significantly mo re soft tissue defects (neural and renal) than were evident in the LM/ Bc fetuses. Overall, the C57BL/6J fetuses were the most sensitive to t he induction of skeletal defects, with a preponderance of defects in t he ossification of the craniofacial bones. It is hypothesized that the reduction in fetal defects was the result of limiting the biotransfor mation of phenytoin to highly teratogenic oxidative metabolites, which interfere with normal fetal growth.