Mechanism of Altered Drug Binding to Serum Proteins in Pregnant Women

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Abstract
The mechanism underlying the impaired serum protein binding of valproic acid (VPA) in pregnancy was exmained in samples collected from 24 healthy women in the last 3 wk of gestation and 15 age-matched nonpregnant female controls. Experiments were performed in vitro using a rapid equilibrium dialysis technique free from in vitro alterations in free fatty acids (FFA). At a total drug concentration of approximately 420 .mu.mol/l, the free VPA fraction was 10.2 .+-. 2.9% (SD) in pregnant women and 4.8 .+-. 1.0% in controls (P < 0.001). Pregnancy was associated with a marked reduction in serum albumin levels but with only a slight, nonsignificant elevation in FFA. Free VPA fraction was negatively correlated with serum albumin levels. A positive correlation between free VPA fraction and FFA was observed in the pregnant group but not in the controls. The only sample collected during labor showed a striking elevation of both free VPA fraction and FFA, in spite of a normal albumin concentration. Scatchard''s plots showed VPA bound to 2 classes of binding sites on the albumin molecule. The number of primary (n1) and secondary (n2) binding sites in pregnant women (n1 = 2.0; n2 = 10.7) was virtually identical to that observed in the controls (n1 = 1.9; n2 = 9.8). The association constants of the primary (k1) and secondary (k2) sites were lower in pregnant women (15.9 .times. 103 and 0.19 .times. 103 l/mol, respectively, vs. 22.6 .times. 103 and 0.33 .times. 103 l/mol in controls), but the difference was not significant. Contrary to findings in animal studies, the defective binding of acidic drugs in sera of pregnant women is largely (although probably not entirely) due to a reduction in albumin concentration. The same may not be true in the perinatal period when marked elevation in maternal FFA can result in drug displacement from binding sites on the albumin molecule.