Adaptation of hepatic ammonia metabolism after chronic valproate administration in epileptics treated with phenytoin.

The effects of phenytoin (PHT) on the modifications of ammonia (NH+4) metabolism caused by sodium valproate (VPA) are here studied in order to identify the drug combinations susceptible of evoking stuporous states in epileptics, a rare condition attributed to a hyperammonemic encephalopathy induced by VPA. During chronic treatment with PHT or VPA-PHT, the acute injection of VPA increases the kidney's output of NH+4. During chronic PHT treatments, the acute injection of VPA modifies the liver's NH+4 metabolism and the arterial hyperammonemia is high (mean = 90 mumol/l). During chronic VPA-PHT treatments, the acute injection of VPA does not affect the hepatic NH+4 metabolism, suggesting that adaptation occurs, and the arterial hyperammonemia is moderate (mean = 60 numol/l). Disturbances of the hepatic adaptive mechanisms may explain certain complications observed during multiple-drug regimens.