Predicting the human teratogenic potential of the anticonvulsant, valproic acid, from a non-human primate model.
The anticonvulsant, valproic acid (VPA) is a suspected human teratogen. This study, employing the rhesus monkey as an animal model, demonstrates that VPA has a significant teratogenic potential in the monkey. Timed pregnant monkeys were exposed orally to VPA at approx. 1X, 10X, and 30X (20, 200, and 600 mg/kg/day, respectively) the human therapeutic dose, daily, during organogenesis (gestation days 21-50). All fetuses of mothers exposed to greater than 1X exhibited some form of embryotoxicity. The highest dose, 30X, was 100% embryolethal, while offspring of the 10X dose group exhibited craniofacial and skeletal defects, and low body weights. Maternal pharmacokinetic parameters and plasma metabolites were determined for VPA on the first and last day of dosing for the 10X dose group. Comparison of the kinetic and metabolite data with that obtained for man indicates that the rhesus monkey is a good model for predicting the teratogenic potential of VPA in the human.
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000818:Animals; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005865:Gestational Age; D006207:Half-Life; D007700:Kinetics; D008253:Macaca mulatta; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D013723:Teratogens; D014635:Valproic Acid / Q000097:blood / Q000378:metabolism / Q000633:toxicity*
D013723:Teratogens; D014635:Valproic Acid