The effects of phenytoin and carbamazepine on serum concentrations of mono-unsaturated metabolites of valproic acid.

Serum concentrations of valproic acid (VPA) and its mono-unsaturated metabolites, 2-propyl-2-pentenoic acid (2-en), 2-propyl-3-pentenoic acid (3-en) and 2-propyl-4-pentenoic acid (4-en), were measured in 36 epileptic patients. The subjects were divided into three subgroups, i.e., receiving VPA alone (n = 20: VPA group), VPA with phenytoin (n = 9: VPA + DPH group), and VPA with carbamazepine (n = 7: VPA + CBZ group). In the VPA group, the correlations between the serum concentration of VPA and those of the metabolites were significantly positive (r = 0.693, P less than 0.01 for 2-en; r = 0.584, P less than 0.01 for 3-en; and r = 0.868, P less than 0.001 for 4-en). The concentration/dose ratio of VPA was significantly lower, and the 4-en/VPA ratio was significantly higher in the VPA + CBZ group than in the VPA group (P less than 0.05). However, DPH had less effect on the concentration/dose ratio of VPA and the 4-en/VPA ratio than CBZ. This may be due partly to the relatively smaller therapeutic dose of DPH. These results suggest a correlation between the serum concentration of VPA and that of 4-en, and an increased metabolic conversion of VPA to 4-en by coadministration of CBZ. High serum concentrations of VPA and concomitant use of CBZ resulted in an elevation of the serum concentration of 4-en, which has been reported to be the most toxic metabolite of VPA.