Elevated plasma glycoproteins in fetal sheep do not bind basic lipophilic drugs

We have evaluated the contribution of nonprecipitable N-acetylneuraminic acid (NANA)-containing plasma glycoproteins found in fetal sheep plasma to the binding of three basic lipophilic drugs: propranolol, lidocaine, and methadone. In adult plasma, the measurement of NANA correlates linearly with the bound fraction of these drugs since the NANA concentration almost exclusively represents the alpha 1-acid glycoprotein (AGP) present, and AGP is the predominant binding protein for these drugs. We found that NANA concentrations in fetal sheep are nearly 20 times those of the mother which, if due to AGP, would suggest an equivalent elevation in binding. Our results opposed this hypothesis since the ratios of bound-to-free drug concentrations in fetal plasma were only 20-36% of the maternal values. From this we conclude that NANA-containing glycoprotein concentrations do not appropriately predict the binding of basic lipophilic drugs in fetal plasma, in contrast to what has been found in adult plasma.