Vaiproic 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

Vaiproic Acid Teratogenicity in Mice after Various Administrationand Phenobarbital-Pretreatment Regimens: The Parent Drug andNot One of the Metabolites Assayed Is Implicated as Teratogen.NAU, H. (1986). Fundam. Appl. Toxicol. 6,662–668. Theantiepileptic drug vaiproic acid (VPA) was administered viafour different routes in the mouse during gestational stagessensitive for interference with neural tube defect formation:a single oral intubation or injection, sc or ip, on Day 8, orinfusion via subcutaneously implanted osmotic minipumps fromDay 7 to 8 of gestation. Embryotoxicity was evaluated on Day18 (incidence of exencephaly, embryolethality and fetal weightretardation). Oral intubation of VPA resulted in significantlylower peak concentrations of VPA as well as lower embryotoxicityas compared to sc and ip administration. The metabolites ofthe ß-, - and -1 oxidation pathways were present inboth maternal serum and gestational tissues in very low concentrations(usually less than 2% of corresponding VPA levels). Infusionof VPA via osmotic minipumps (lower steady-state VPA levelsas compared to peak levels following injection of VPA) resultedin embryolethality and fetal weight retardation, but littleexencephaly. The metabolic pattern was similar in all four administrationexperiments. Phenobarbital pretreatment of the dams (previouslyshown to reduce VPA serum concentrations and induce the and-1 oxidation pathways) reduced the embryotoxicity of VPA. Theseresults suggest that VPA embryotoxicity is mediated by the parentdrug, and not one of the metabolites considered in this study.