Teratogenesis of calcium valproate in rats

Abstract

Studies were conducted to determine the teratogenic potential of the calcium salt of valproic acid in rats when given orally at doses of 600, 150, and 50 mg/kg on days 6–15 of gestation. The sodium salt of valproic acid was used as a reference agent at a dose level of 600 mg/kg. The administration of 600 mg/kg/day of either calcium or sodium valproate resulted in transient, severe sedation in the dams. Four dams receiving 600 mg/kg of either salt died during the experiment, with deaths occurring between day 7 and 11 of gestation. Food consumption and body weight gain were significantly reduced during the dosing period with both salts at dose levels of 600 mg/kg. Embryotoxicity at the high doses (600 mg/kg) with either salt was manifested by increases in fetal resorption, reduced body weights, and significantly increased incidence of supernumerary ribs and bifid vertebral centra among the surviving fetuses. A teratogenic effect was evident at 600 mg/kg with either salt of valproic acid. Seven of 16 fetuses from dams given the calcium salt were abnormal. Findings included one with omphalocele and six others with skeletal malformations. Eleven of 24 fetuses from dams given the sodium salt were abnormal: three littermates had bilateral ectrodactyly of the rear feet and malformed vertebral centra and eight others had skeletal malformations. No teratogenic effect was evident among the fetuses from dams given 150 mg/kg calcium salt. Embryotoxicity was demonstrated by a significant increase in the incidence of supernumerary ribs. No adverse effect was observed among the fetuses from dams given 50 mg/kg of the calcium salt.