Sodium valproate associated with phenobarbital: effects on ammonia metabolism in humans

Treatment with sodium valproate (VPA) in association with phenobarbital (PB) is accompanied by a greater systemic hyperammonemia than treatment by VPA alone. The anatomical origins of this difference were studied by injecting a dose of 1,500 mg VPA i.v. into six unmedicated patients and six epileptics chronically treated with PB and measuring the ammonium (NH4+) concentration difference between arterial blood and renal, hepatic, internal jugular, and femoral venous blood. In unmedicated patients, arterial [NH4+] rose moderately, secondary to an increased amount of NH4+ released into the general circulation by the kidney; the hepatic metabolism of NH4+ remained normal. In epileptics treated with PB, arterial [NH4+] rose massively, partly as a result of the increased NH4+ release by the kidney and partly because of disturbance of the hepatic metabolism of NH4+. These results provide a clearer understanding of the potentiation of the secondary effects of VPA by PB.