Differences in in vitro binding of diazepam and N-desmethyldiazepam to maternal and fetal plasma proteins at birth: relation to free fatty acid concentration and other parameters

The in vitro protein binding of diazepam and its major plasma metabolite, N-desmethyldiazepam (DMD), was measured in women at full term of pregnancy, in mixed cord plasma (fetal plasma), and in control subjects. The free fraction of both drugs was determined by ultrafiltration at 37°. The mean free fraction of diazepam was 0.023 ± 0.0043 in control subjects and rose to 0.040 ± 0.0071 in women at term, whereas in their fetuses the free fraction was 0.021 ± 0.0057. The unbound fraction of DMD was 0.030 ± 0.0084 in control subjects, 0.052 ± 0.015 in women at term, and 0.035 ± 0.010 in fetal plasma. The free fractions of both compounds differed in women at term and in their fetuses. The higher free fraction of the two drugs in maternal plasma than in cord plasma may be explained by elevated maternal concentrations of free fatty acids (and triglycerides), which may act as displacing agents in maternal plasma. The higher binding of these drugs in fetal plasma than in maternal plasma may explain their cumulation in vivo and may be responsible for the frequently observed adverse effects of maternal diazepam treatment on the newborn infant. Clinical Pharmacology and Therapeutics (1983) 34, 220–226; doi:10.1038/clpt.1983.156