Disposition of valproic acid in maternal, fetal, and newborn sheep I: Placental transfer, plasma protein binding, and clearance

Separate 24-h maternal and fetal infusions of valproic acid (VPA) were admi nistered to five pregnant sheep at 125 to 138 days gestation (term similar to 145 days) to determine maternal-fetal disposition. The pharmacokinetics of VPA were also investigated in five newborn 1-day-old lambs after a 6-h d rug infusion. Plasma, urine, and amniotic and fetal tracheal fluid samples were analyzed for VPA using gas chromatography-mass spectrometry. During ma ternal drug infusion, the average steady-state fetal/maternal unbound VPA p lasma concentration ratio was 0.81 +/- 0.09. Unbound maternal-to-fetal VPA placental clearance (69.0 +/- 20.2 ml/min/kg) was similar to that in the ot her direction (61.9 +/- 24.2 ml/min/kg); this indicates passive placental d iffusion and intermediate placental permeability of VPA in sheep. Newborn u nbound VPA clearance (0.66 +/- 0.28 ml/min/kg) was much lower than in the m other (5.4 +/- 2.7 ml/min/kg) or the fetus (62.1 +/- 22.4 ml/min/kg), and e xhibited pronounced Michaelis-Menten characteristics. The elimination half- life of the drug was much longer in the newborn (18.6 +/- 2.6 h) relative t o the mother (5.6 +/- 1.4 h) and the fetus (4.6 +/- 1.9 h). Thus, VPA elimi nation in newborn lambs is much slower as compared with adult sheep, a situ ation similar to that in humans. Plasma protein binding of VPA was saturabl e, with similar VPA binding capacities and affinities in maternal and fetal plasma. VPA was extensively displaced from binding sites in the newborn la mb during the first 1 to 2 days of life, possibly because of increased plas ma free fatty acid concentrations at birth. Thereafter, newborn plasma appe ared to have a similar VPA binding capacity but lower affinity compared wit h the mother and the fetus.