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.