Preclinical toxicology of the anticonvulsant calcium valproate.

The oral toxicity of the anticonvulsant calcium valproate with selected comparisons to valproic acid and sodium valproate was evaluated in mice, rats and Beagle dogs. Median lethal doses of the three forms of valproate in rodents ranged from 1100 to 3900 mg/kg. Clinical signs in acute studies and reductions in body weight or body weight gain and food consumption at high doses in rats and dogs during 2-, 13- and 52-week studies were considered to be central nervous system related. In the 13-week study in rats (calcium valproate at 200, 400, 800, 1200 and 1600 mg/kg and sodium valproate at 1200 mg/kg), reduced plasma globulin levels and low white blood cell counts due to suppressed neutrophil maturation were noted at doses of 800 mg/kg and higher. Platelet counts were reduced at 1200 and 1600 mg/kg. Testicular atrophy occurred at 1200 and 1600 mg/kg. In dogs given calcium valproate at 100, 200 and 400 mg/kg for 13 weeks, testicular atrophy was seen at 400 mg/kg and mild hepatocellular changes at all doses. In rats given calcium valproate at 125, 250 and 500 mg/kg for 1 year, reduced plasma protein and globulin levels and a dose-dependent increased incidence and severity of atrophic pancreatitis were noted at 250 and 500 mg/kg. Calcium valproate, given for 1 year to dogs at doses of 50, 100 and 200 mg/kg, was well tolerated. These studies indicated that calcium valproate has a toxicity profile similar to other forms of valproate.