The significance of plasma protein binding on the fetal/maternal distribution of drugs at steady-state.
Maternal and fetal plasma differ in their concentrations of the important drug binding plasma proteins, albumin and alpha 1-acid glycoprotein, with albumin being slightly more concentrated in fetal plasma, and alpha 1-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Hill
M D
MD
George Washington University, School of Medicine and Health Sciences, Department of Pharmacology, Washington.
Abramson
F P
FP
D001798:Blood Proteins / Q000378:metabolism*; D005260:Female; D005326:Fetal Proteins / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008431:Maternal-Fetal Exchange; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011247:Pregnancy; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*
D001798:Blood Proteins; D005326:Fetal Proteins; D004364:Pharmaceutical Preparations; D012709:Serum Albumin