Effect of stiripentol dose on phenytoin-induced teratogenesis in a mouse model.
OBJECTIVE
Previous studies have suggested that polytherapy by design may aid in the management of human pregnancies complicated by epilepsy. However, mechanistic parallels must be drawn between the models of teratogenesis and human pregnancies, and doses of the second agent given to minimize side-effects 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 metabolism by STP in vitro decreased production of reactive phenytoin (PHT) metabolites.


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 examined for developmental anomalies. [14C]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 [14C] was measured.


RESULTS
There were no dose-related differences in the frequency of fetal malformations per litter among groups treated with STP alone. However, STP (all doses) reduced the frequency of PHT-induced malformations. Covalent binding of [14C]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 support the concept of polytherapy by design to reduce the risk of teratogenesis associated with PHT.
Finnell
R H
RH
Department of Veterinary Anatomy and Public Health, Texas A&M University, College Station, USA.
Bennett
G D
GD
Mather
G G
GG
Wlodarczyk
B
B
Bajpai
M
M
Levy
R H
RH
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000517:prevention & control*; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity*; D002250:Carbon Radioisotopes; D004148:Dioxolanes / Q000097:blood / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D009249:NADP / Q000494:pharmacology; D009928:Organ Specificity; D010672:Phenytoin / Q000097:blood / Q000633:toxicity*; D011247:Pregnancy
D000927:Anticonvulsants; D002250:Carbon Radioisotopes; D004148:Dioxolanes; D009249:NADP; D010672:Phenytoin; C021092:stiripentol