Determination of valproic acid kinetics in patients during maintenance therapy using a tetradeuterated form of the drug.

A method has been developed for measuring concentrations of valproic acid and, with stable isotopes, labelled forms of VPA, in the plasma of patients undergoing maintenance therapy. One tetradeutero isomer of valproic acid-di-(2,3-dideuteropropyl) acetic acid-has been synthesized for administration to patients. A [2H14]valproic acid-diheptadeuteropropyl acetic acid-was synthesized as the internal standard. After isolation from body fluids the acids were methylated with diazomethane. The McLafferty fragments of the methyl esters were used for mass spectrometric quantification. It was demonstrated that the [2H4]valproic acid used behaves kinetically like the unlabelled drug in the human body. One dose of [2H4]valproic acid was given as a pulse dose to epileptic patients and the elimination profile was measured during continuous normal treatment. The half-life of valproic acid in patients under barbiturate or carbamazepine co-medication was reduced to at least half the value found after single dose administration to healthy volunteers.