Acheampong A A, Abbott F S, Orr J M, Ferguson S M, Burton R W
J Pharm Sci. 1984 Apr;73(4):489-94. doi: 10.1002/jps.2600730415.
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 microgram/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 omega-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.
二 - [（3,3,3 - 2H₃）丙基]乙酸，一种丙戊酸的十六氘代类似物，被合成出来，并将其药代动力学性质与丙戊酸进行了比较。采用选择离子监测的气相色谱 - 质谱法测定血清和唾液中丙戊酸和[2H]丙戊酸的浓度。唾液药物水平的测量精度良好，低至0.1微克/毫升。在一名人类志愿者的单剂量研究中证明了丙戊酸和[2H]丙戊酸的动力学等效性。观察到ω - 氧化存在同位素效应，但代谢差异不足以使[2H]丙戊酸在生物学上不等效。在同一名志愿者中评估了应用[2H]丙戊酸来测定稳态浓度下丙戊酸的动力学情况。用[2H]丙戊酸获得的动力学数据与先前报道的丙戊酸值一致，包括在单剂量和稳态实验之间观察到的动力学差异。发现在多剂量条件下，唾液中丙戊酸水平与血清中总丙戊酸具有良好的相关性（r = 0.953）。发现唾液丙戊酸与血清中游离丙戊酸的比值存在浓度依赖性，在丙戊酸血清浓度高时观察到低比值。
