Bowdle T A, Patel I H, Levy R H, Wilensky A J
Eur J Clin Pharmacol. 1982 Oct;23(4):343-7. doi: 10.1007/BF00613618.
The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37 degrees C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34-182% (p less than 0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50-87%, p less than 0.01) than in fasting samples (10-50%, p less than 0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (P less than 0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.
在6名健康成年受试者中研究了游离脂肪酸水平的生理变化对丙戊酸体内血浆蛋白结合的影响。在稳态下进食期间的12小时给药间隔内以及27小时禁食期间采集了14份血样。游离分数和丙戊酸盐总浓度分别通过平衡透析和气相色谱法测定。游离脂肪酸水平从新鲜样品以及在37℃孵育12小时的样品中测定，后者是为了模拟平衡透析条件。禁食导致所有受试者的血清游离脂肪酸水平升高，范围为34%-182%（p<0.01）。孵育也导致游离脂肪酸水平升高，进食样品中升高得更多（50%-87%，p<0.01），高于禁食样品（10%-50%，p<0.01）。禁食导致所有受试者合并后的平均游离分数增加9%（P<0.01）。对180组游离分数、丙戊酸盐总浓度和游离脂肪酸水平值的回归分析表明，丙戊酸盐浓度占游离分数变化的17%，游离脂肪酸水平占37%。尽管游离分数增加表明在这些条件下丙戊酸的内在清除率降低（即代谢降低），但禁食并未改变平均清除率。
