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.