The pharmacokinetics of valproic acid in pregnant sheep after maternal and fetal intravenous bolus administration

Abstract

The pharmacokinetics and disposition of valproic acid (VPA) have been assessed in pregnant sheep after both maternal and fetal iv bolus administration. The time course of VPA and 16 of its metabolites was followed in maternal and fetal arterial blood, amniotic fluid, and fetal tracheal fluid for 48 hr after administration. Fetal blood gas, acid-base, metabolic, cardiovascular, and fetal breathing activity parameters were also monitored. The disposition of VPA in maternal serum is best described by a biexponential function with a terminal elimination half-life of 2.13 +/- 0.49 hr and volume of distribution of 0.242 +/- 0.036 liter/kg. VPA transfer to fetal serum and other fetal fluids was rapid after drug administration. There was significant fetal exposure to VPA after maternal dosing (mean AUCinfinityFA/AUCinfinityMA = 0.410 +/- 0.118). Similarly, the disposition of VPA in fetal serum after fetal dosing is best described by a biexponential decay with a terminal elimination half-life of 3.37 +/- 1.37 hr. Once again, VPA transfer to other fluids was rapid. However, unlike basic compounds studied previously, VPA did not accumulate extensively in either amniotic or fetal tracheal fluid. The following metabolites were detected after drug administration in these experiments: (E)- and (Z)-2-ene VPA, (E)- and (Z)-3-ene VPA, 4-ene VPA, 3-keto VPA, 4-keto VPA, 3-OH VPA, 4-OH VPA, 5-OH VPA, and 2-PGA. Both maternal and fetal bolus administration of VPA elicited a significant reduction in fetal breathing movements, which may be attributed to the drug's action on gamma-aminobutyric acid dynamics in the central nervous system (CNS). This suggests that the significant fetal exposure to VPA may produce further CNS-related effects in utero.