Valproic acid teratogenicity in mice after various administration and phenobarbital-pretreatment regimens: The parent drug and not one of the metabolites assayed is implicated as teratogen

Abstract

The antiepileptic drug valproic acid (VPA) was administered via four different routes in the mouse during gestational stages sensitive for interference with neural tube defect formation: a single oral intubation or injection, sc or ip, on Day 8, or infusion via subcutaneously implanted osmotic minipumps from Day 7 1 2 to 8 1 2 of gestation. Embryotoxicity was evaluated on Day 18 (incidence of exencephaly, embryolethality and fetal weight retardation). Oral intubation of VPA resulted in significantly lower peak concentrations of VPA as well as lower embryotoxicity as compared to sc and ip administration. The metabolites of the β-, ω- and ω-1 oxidation pathways were present in both maternal serum and gestational tissues in very low concentrations (usually less than 2% of corresponding VPA levels). Infusion of VPA via osmotic minipumps (lower steady-state VPA levels as compared to peak levels following injection of VPA) resulted in embryolethality and fetal weight retardation. but little exencephaly. The metabolic pattern was similar in all four administration experiments. Phenobarbital pretreatment of the dams (previously shown to reduce VPA serum concentrations and induce the ω and ω-1 oxidation pathways) reduced the embryotoxicity of VPA. These results suggest that VPA embryotoxicity is mediated by the parent drug, and not one of the metabolites considered in this study.