Differential binding of warfarin to maternal, foetal and non-pregnant sera and its clinical implications

The object of this study was to determine whether differential binding of sodium warfarin in paired maternal and cord sera accounts for its adverse effects on the foetus. In-vitro binding of sodium warfarin to human serum albumin in maternal, foetal, and non-pregnant (control) subjects was determined by equilibrium dialysis at 37 degrees C. Our data suggest that at therapeutic concentrations, sodium warfarin has a single high affinity binding site on human serum albumin with an association constant of 1.65 x 10(-3) M. Serum albumin concentration in the control sera (4.42 +/- 0.08 g dL(-1)) was comparable with that in the cord sera (4.54 +/- 0.26 g dL(-1)) but was significantly higher (P < 0.01) than the maternal levels (4.03 +/- 0.21 g dL(-1)). Binding data indicate that the fraction of unbound warfarin in the foetal sera (6.8 +/- 1.9 g dL(-1)) was significantly higher than in the maternal (3.60 +/- 1.3 g dL(-1); P < 0.01) and nonpregnant sera (1.96 +/- 0.6 g dL(-1) P < 0.001). The maternal and foetal fractions of free warfarin were directly proportional to the concentrations of free fatty acids (y = 1268 - 110x; r = 0.93; P < 0.001), and bilirubin (y = 8.7 + 1.4x; r = 0.91; P < 0.001), respectively. This study indicates that warfarin was more strongly bound in the maternal sera than in the foetal sera; this was probably because of the competitive and allosteric effect of free fatty acid and bilirubin in the maternal and foetal sera, respectively. The clinical significance of this observation is discussed in this paper.