Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats

This study was undertaken to assess the pharmacokinetics and developmental toxicity of the anticonvulsant, valproic acid (VPA), a human teratogen, in Sprague-Dawley rats. Oral administration of 200-800 mg/kg VPA (5-20x human therapeutic dose) from Gestational Days (GD) 8 to 17 resulted in increasing maternal toxicity at the higher doses with 100% maternal lethality at 800 mg/kg. Although there was an increased incidence of resorptions at 600 mg/kg (48 +/- 43%) compared to controls (18 +/- 24%), it was not statistically significant. Fetal examination on GD 20 revealed dose-dependent fetal growth retardation (p less than or equal to 0.05) as evidenced by decreased fetal weight and length in addition to underossification of both the axial and appendicular skeleton. The incidence of skeletal defects, including abnormal vertebrae, ribs, and craniofacial dysmorphia, also increased with higher doses of VPA. Cardiac anomalies observed in the two highest treatment groups consisted of great vessel malformations with or without associated ventricular septal defects (VSDs). Urogenital defects were also noted in the 600 mg/kg group. The plasma elimination half-life on GD 8 was 1.0 +/- 0.3 hr at 200 mg/kg and 2.3 +/- 0.7 hr at 600 mg/kg. Maximal concentrations of total and free drug were 341 +/- 18 micrograms/ml and 181 +/- 11 micrograms/ml, respectively, in the low-dose group and 911 +/- 379 micrograms/ml and 542 +/- 224 micrograms/ml in the high-dose group. No significant changes in any pharmacokinetic parameters (t1/2, AUC, Cmax, tmax) were observed over the 10-day treatment period at either dose level.