Metabolite profiles in patients on high-dose valproate monotherapy

To investigate the mechanism of valproate (VPA)-induced hepatotoxicity, we measured the serum and urine metabolites of VPA in high-dose VPA monotherapy by GC/MS/SIM and discussed the relationship between liver function and beta-oxidation, omega-, (omega-1)-oxidation metabolites and 4-en-VPA. In high-dose VPA monotherapy, the concentrations of beta-oxidation metabolites were not increased except for 2-en-VPA, but the concentrations of {omega + (omega-1)}-oxidation metabolites and of 4-en-VPA were increased about 4-5 times compared to those of standard dose VPA monotherapy. Serum GOT was not significantly correlated to 4-en-VPA and the ratio of beta-oxidation/{omega + (omega-1)} oxidation metabolites of VPA in serum. In high-dose VPA monotherapy, it is speculated that the beta-oxidation of VPA in the mitochondria reached the saturation point. However, instead of the beta-oxidation, the {omega + (omega-1)}-oxidation in microsomes was increased. We could not find significant relationship between the formation of toxic metabolites of VPA and liver dysfunction. Our data in VPA monotherapy suggest that the mechanisms of VPA-induced fatal hepatotoxicity cannot be explained by decreased beta-oxidation, increased omega-oxidation and increased 4-en-VPA level.