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

Article abstract of DOI:10.1002/jps.2600730415

Di-([13,3,3-²H₃]propyl)acetic acid, a hexadeuterated analogue of valproic acid, was synthesized and its pharmacolinetic 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.