Use of hexadeuterated valproic acid and gas chromatography-mass spectrometry to determine the pharmacokinetics of valproic acid

Di‐([3,3,3−2H3]propyl)acetic acid, a hexadeuterated analogue of valproic acid, was synthesized and its pharmacokinetic properties compared with valproic acid. Concentrations of valproic acid and [2H]valproic acid in serum and saliva were determined by GC‐MS using selected‐ion monitoring. Saliva drug levels were measured with good precision down to 0.1 μg/mL. Kinetic equivalence of valproic acid and [2H]valproic acid was demonstrated in a single‐dose study in a human volunteer. An isotope effect was observed for ω‐oxidation, but the difference in metabolism was not sufficient to make [2H]valproic acid biologically nonequivalent. The application of [2H]valproic acid to determine the kinetics of valproic acid under steady‐state concentrations was evaluated in the same volunteer. The kinetic data obtained with [2H]valproic acid was consistent with previously reported values for valproic acid including kinetic differences observed between single‐dose and steady‐state experiments. Saliva levels of valproic acid were found to give a good correlation (r =0.953) with total serum valproic acid under multiple‐dose conditions. A concentration dependence was found for the ratio of saliva valproic acid to free valproic acid in serum, low ratios being observed at high serum concentrations of valproic acid.