Valproate and carbamazepine comedication changes hepatic enzyme activities in sera of epileptic children

Previous observation that valproic acid (VPA) and carbamazepine (CBZ) caused hepatic damage prompted us to investigate the effects of VPA or CBZ monotherapy and VPA + CBZ comedication on the number of hepatic enzyme activities in sera of epileptic children. This study compares alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) activities in sera of children treated with VPA (n=42), or CBZ (n=36) taken as a monotherapy, with VPA + CBZ combined therapy (n=36). The effect of VPA alone is greater on the activity of AST than on other enzymes, while CBZ therapy changes primarily the activities of GGT. The mean catalytic activity of AST was significantly elevated in groups on VPA, CBZ and VPA + CBZ treatment (2.02-, 1.49- and 1.45-fold increase, respectively) as compared to the control values. Changes in the ALT activity followed different patterns. The maximal increase was observed in the CBZ group with a smaller increase in the group on VPA + CBZ polytherapy, whereas only 15% of patients receiving VPA showed an average 1.38-fold increase of the mean enzyme activity. Increase in the catalytic activity of GGT probably reflects the induction produced by the CBZ treatment, either alone or in combination. Children on CBZ monotherapy showed an increase of mean catalytic activity of about twofold in 56% of patients. Children on VPA + CBZ comedication showed a similar behaviour, while VPA alone produced a moderate (1.44-fold) increase in 23% of children. However, concentrations of VPA and CBZ in sera of patients receiving monotherapy were within the expected therapeutic limits, whereas subtherapeutic levels of VPA were found in 30% of children on VPA + CBZ comedication. We propose that individual dosage adjustment in VPA + CBZ polytherapy should be combined with monitoring of relevant enzyme activities in serum.