Hyperammonaemia and hepatotoxicity during chronic valproate therapy: enhancement by combination with other antiepileptic drugs

Erythrocyte (ENH3) and plasma (PNH3) ammonia levels, liver function tests and plasma valproate concentration were measured in 81 epileptic patients, comprising three therapeutic groups: Group 1 (23 patients) received sodium valproate (VPA) monotherapy, group 2 (33 patients) received sodium valproate combined with phenytoin, carbamazepine, phenobarbitone and/or primidone and group 3 (25 patients) received one or more of these anti-epileptic drugs without sodium valproate. The mean ENH3 and PNH3 of patients in group 1 (41.1 +/- 30.7 mumol l-1 and 37.1 +/- 31.8 mumol l-1, respectively) and group 2 (44.5 +/- 21.3 and 37.6 +/- 21.4 mumol l-1, respectively) were significantly (P less than 0.01) higher than those in group 3 (28.7 +/- 10.6 and 21.5 +/- 7.8 mumol l-1, respectively) and the reference range (30.1 +/- 7.9 and 20.8 +/- 5.7 mumol l-1, respectively). Hyperammonaemia was more prevalent amongst patients in group 2, for both ENH3 (45.5%) and PNH3 (54.6%), than amongst patients in group 1 (30.4% and 52.2%, respectively) and group 3 (8% and 8%, respectively). There was a significant (P less than 0.05) positive correlation between plasma VPA and total bilirubin concentrations. Chronic VPA therapy was also associated with an increase in bilirubin concentrations measured on average four months apart.