Nau H, Krauer B
J Clin Pharmacol. 1986 Mar;26(3):215-21. doi: 10.1002/j.1552-4604.1986.tb02937.x.
The protein binding (expressed as percent free drug fraction) of the antiepileptic drug valproic acid (VPA) was studied in 65 fetus-mother pairs from weeks 13 to week 41 of gestation. The fetal free fractions (expressed as percent of total concentrations) of VPA were exceedingly high (greater than 50%) during weeks 13 to 16 of gestation; these values decreased to 20% by week 20 and further decreased gradually to 10% at term. There was a highly significant negative correlation between free VPA fractions and fetal albumin concentrations. Maternal free fractions of VPA gradually increased from 10% during early pregnancy to 20% at term. The free fractions of VPA were significantly higher in mothers who had received oxytocin. Thus, protein binding in the fetus exceeded that of the mother at term, whereas the converse was true during early gestation. These results agree with previous in vivo findings. It is likely that the free concentrations in the mother determine the drug effects and toxicity in both the mother and the fetus. Intermittent drug administration--particularly of large single doses--could result in a transient increase of the free concentrations of VPA, particularly because of the strong concentration dependence of VPA protein binding. Increased free fractions can also be expected from increased concentrations of displacing agents of endogenous or exogenous origin (other drugs).
在65对妊娠13周至41周的胎儿 - 母亲对中，研究了抗癫痫药物丙戊酸（VPA）的蛋白结合情况（以游离药物分数百分比表示）。在妊娠13至16周期间，VPA的胎儿游离分数（以总浓度的百分比表示）极高（大于50%）；这些值在妊娠20周时降至20%，并在足月时逐渐进一步降至10%。游离VPA分数与胎儿白蛋白浓度之间存在高度显著的负相关。VPA的母体游离分数从妊娠早期的10%逐渐增加到足月时的20%。接受催产素的母亲中VPA的游离分数显著更高。因此，足月时胎儿中的蛋白结合超过母亲，而在妊娠早期则相反。这些结果与先前的体内研究结果一致。母亲体内的游离浓度可能决定母亲和胎儿体内的药物作用和毒性。间歇性给药——尤其是大剂量单次给药——可能导致VPA游离浓度的短暂升高，特别是因为VPA蛋白结合具有很强的浓度依赖性。内源性或外源性（其他药物）置换剂浓度增加也可能导致游离分数增加。
