The Significance of Plasma Protein Binding on the Fetal/Maternal Distribution of Drugs at Steady-State

SummaryMaternal and fetal plasma differ in their concentrations of the important drug binding plasma proteins, albumin and α1acid glycoprotein, with albumin being slightly more concentrated in fetal plasma, and α1-acid glycoprotein being only 37% of the maternal concentration at term. In general, these differences relate linearly to the bound to free concentration ratio of drugs associated with these proteins. Although only the free concentration is generally considered to be the pharmacologically active form, these differences can dramatically affect the total concentration and relative distribution of drugs between maternal and fetal plasma.In order to test our hypothesis that plasma protein binding is the major determinant of fetal/maternal drug distribution at steady-state, we examined whether fetal binding could be predicted from adult binding information. Data from studies of maternal, plasma protein binding were used to predict fetal plasma protein binding based solely on the differences in protein concentrations. These predictions were compared with observed fetal binding data. This analysis showed a slope near unity and a high correlation (r2 = 0.900) which implies that there are no significant differences between the binding affinities of these proteins. A similar analysis performed using data on drug binding in non-pregnant adults gave an r2 or 0.971.Having established that fetal plasma proteins bind drugs similarly to their maternal counterparts, fetal/maternal plasma drug concentration ratios (F/M) were predicted for various drugs using information from literature on the drug’s adult plasma protein binding, the protein to which it binds, and the fetal and maternal plasma concentrations of that binding protein. This information was compared with data from studies which observed the fetal/maternal plasma concentration ratio of these drugs at steady-state. The observed F/M ratio was correlated with the predicted F/M values for the 35 drugs (r2 = 0.473, p < 10−5. When considering only studies done at term the correlation coefficient increased to 0.558. This analysis was subject to the limitations of comparing mean data from different studies.The fact that nearly half or more of the variability of the transplacental drug concentration ratios at steady-state is explainable by the plasma protein concentration gradient, despite between-study variability, leads us to conclude that it is the most significant factor in establishing the F/M ratio at steady-state.