The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats

Abstract

Valproate is a valuable anticonvulsant which is associated with hepatotoxicity in some patients. In concentrations in the range found in man during valproate therapy (0.1-1.0 mM), it inhibited pyruvate and palmitate oxidation, urea synthesis and gluconeogenesis by 30-50% in isolated rat hepatocytes. Valproate (100 mg/kg body weight) is also hypoglycaemic and hypoketonaemic in fasted rats. All these inhibitions can be explained in terms of the accumulation of valproyl-CoA and its further metabolites in the matrix of hepatic mitochondria. Although these inhibitions are only partial, and normally well tolerated, they could significantly impair liver function when there is an additional insult, such as may occur with multiple drug therapy or if there is already an inborn error of metabolism. Such an association with inborn errors may explain the higher incidence of valproate-associated toxicity in children. It may be of more value to measure blood urea and ammonia concentrations routinely shortly after starting valproate therapy than to do conventional liver function tests.