Effect of stiripentol dose on phenytoin-induced teratogenesis in a mouse model

Purpose: Previous studies have suggested that polytherapy by design may aid in the management of human pregnancies complicated by epilepsy. However, m echanistic parallels must be drawn between the models of teratogenesis and human pregnancies, and doses of the second agent given to minimize side-eff ects must be justified. This study sought to determine the lowest dosage of stiripentol (STP) protective against phenytoin-induced teratogenesis in a mouse model, and to determine mechanistically if inhibition of oxidative me tabolism by STP in vitro decreased production of reactive phenytoin (PHT) m etabolites. Methods: Pregnant SWV mice were assigned to control or treatment groups of STP alone, PHT alone, or PHT with ascending doses of STP coadministration. Treatments continued from Day 6 to Day 18 of gestation when fetuses were ex amined for developmental anomalies. [C-14]PHT was incubated in mouse liver microsomes with and without NADPH and in the presence or absence of STP or piperonyl butoxide, Covalent binding of [C-14] was measured. Results: There were no dose-related differences in the frequency of fetal m alformations per litter among groups treated with STP alone. However, STP ( all doses) reduced the frequency of PHT-induced malformations. Covalent bin ding of [C-14]PHT was NADPH-dependent and was inhibited by either piperonyl butoxide or STP. Conclusions: The beneficial effects of STP occurred at concentrations below the therapeutic range for its anticonvulsant effects. These results suppor t the concept of polytherapy by design to reduce the risk of teratogenesis associated with PHT. (C) 1999 Elsevier Science Inc.