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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.