Effect of valproic acid on zinc metabolism in the rat

Previous studies have suggested that the mechanism of valproic acid (VPA) hepatotoxicity may involve a drug-induced Zn deficiency. To test this hypothesis, the uptake of 65Zn or tissue Zn concentration was determined in plasma, liver, bone, kidney, and brain of adult male rats, administered parenteral VPA according to one of 3 schedules: 750 mg/kg; 500 mg/kg; and 100 mg/kg/day X 7 days. Histopathological changes in liver and weight loss were observed in rats 5 days after administration of VPA (750 mg/kg). The plasma Zn level in VPA toxic rats was significantly depressed compared to saline-injected controls, although the Zn content of liver and bone was unaffected. Furthermore, tissue uptake of 65Zn was not altered in rats 6 h after receiving VPA 500 mg/kg or after chronic administration at 100 mg/kg/day. On the basis of the present study, there is no evidence that Zn deficiency is induced by hepatotoxic doses of VPA in rats.