Serum protein binding of valproic acid in fetus-mother pairs throughout pregnancy: correlation with oxytocin administration and albumin and free fatty acid concentrations.

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).