Serum protein binding of diazepam and propranolol in the feto-maternal unit from early to late pregnancy.

Paired samples of maternal and fetal serum were obtained in 65 pregnancies between 13 and 41 weeks gestation. Concentrations of albumin, alpha 1-acid glycoprotein (alpha 1-AGP) and free fatty acids (FFA) were estimated in all samples and the in-vitro binding of diazepam and propranolol was estimated. The free fraction of diazepam in fetal serum was very high in early gestation and decreased with advancing gestation to reach maternal values around the 30th week. After 35 weeks gestation, values were generally lower in fetal than in maternal serum. Fetal serum binding of diazepam correlated with fetal albumin levels and gestational age. The ratio of the fetal/maternal free diazepam fraction correlated negatively with the fetal/maternal serum albumin concentration ratio. The maternal/fetal free diazepam fraction ratio correlated positively with gestational age. The free fraction of propranolol in fetal serum was higher than in maternal serum in early pregnancy and decreased with advancing gestation but always remained higher than the maternal values. The fetal/maternal free propranolol fraction ratio was negatively correlated with the fetal/maternal alpha 1-AGP serum concentration ratio. The maternal/fetal free propranolol fraction ratio was positively correlated with gestational age. Serum protein binding of propranolol was correlated with serum albumin concentrations in fetal samples but not in maternal samples. Serum FFA concentrations were not correlated with serum protein binding except for maternal serum binding of diazepam. For toxicological reasons it is advisable to monitor maternal blood for free concentrations of drugs that exhibit concentration-dependent protein binding or which can be displaced from binding sites by other drugs or endogenous compounds such as FFA.