Valproate metabolites in high-dose valproate plus phenytoin therapy.

PURPOSE: We wished to determine the relation between liver function, beta-, and omega-, and omega-1-oxidation metabolites and 4-en-valproate (VPA). METHODS: We measured the serum levels of VPA and its metabolites in children and adolescent receiving high-dose VPA plus phenytoin (PHT) therapy using gas chromatography-mass spectrometry with selected ion monitoring (GC/MS/ SIM). RESULTS: In high-dose VPA plus PHT polytherapy, the total VPA serum concentration was distinctly low, the concentrations of total beta-oxidation metabolites were decreased, the percentage values of VPA (percent of VPA) of total beta-oxidation metabolites were increased, and the E-2-en-VPA/3-keto-VPA ratios were decreased, as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT polytherapy, 4-en-VPA (microM) was decreased and the concentrations of [omega + (omega-1)]-oxidation metabolites (microM) were decreased as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT, serum glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and lactic dehydrogenase (LDH) did not correlate significantly with the ¿beta/omega + (omega-1)¿ metabolites ratio and 4-en-VPA levels, but serum GOT, GPT, and LDH were increased as compared with those in high-dose VPA therapy. We were not able to establish a significant relation between the formation of metabolites of VPA metabolites and liver dysfunction in patients receiving high-dose VPA and PHT concurrently. CONCLUSIONS: Metabolic levels do not appear to be a reliable predictor of hepatotoxicity in children receiving pharmacological antiepileptic drug (AED) therapy.

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.

Effect of L-carnitine supplementation on acute valproate intoxication.

We analyzed urinary valproate (VPA) metabolites and carnitine concentrations in a child who accidentally ingested 400 mg/kg VPA. The concentration of 4-en VPA, the presumed major factor in VPA-induced hepatotoxicity, was markedly increased, without liver dysfunction or hyperammonemia. The other major abnormality was decreased beta-oxidation and markedly increased omega-oxidation. After L-carnitine supplementation, VPA metabolism returned to normal. The level of valproylcarnitine was not increased and therefore was not affected by L-carnitine. L-Carnitine may be useful in treating patients with coma after VPA overdose.