Sensitive capillary gas chromatographic-mass spectrometric method for the therapeutic drug monitoring of valproic acid and seven of its metabolites in human serum. Application of the assay for a group of pediatric epileptics.

A sensitive capillary gas chromatographic-mass spectrometric method for the determination of valproic acid and 7 of its metabolites is described. It is based on the selected-ion monitoring of the tert.-butyldimethylsilyl derivatives using N-(tert.-butyldimethylsilyl)-N-methyl-trifluoracetamid (MTBSTFA) as the derivatization reagent. The limits of detection for valproic acid and its metabolites are in the low ng/ml-range, except for the 4-hydroxy metabolite with a limit of detection of 100 ng/ml. The method has been tested against an established GC method for valproic acid. The assay has been used for therapeutic drug monitoring in epileptic pediatric patients. The concentrations of the omega- and omega 1-oxidation metabolites in a group of patients receiving additional antiepileptic drugs were found to be significantly enhanced compared to the levels found in a monotherapy group.