Transplacental transfer and biotransformation studies of valproic acid and its glucuronide(s) in the perfused human placenta.

Abstract

Transplacental transfer and biotransformation of valproic acid (VPA) and its acyl glucuronide conjugate (VPA-G) were investigated in the isolated perfused term human placenta. In peripheral lobules perfused under dual (maternal and fetal) recirculation for 6 hr, VPA was readily transferred, reaching equilibrium (stable maternal and fetal VPA concentrations with no transplacental gradient of unbound VPA) within 1.5 hr. Metabolism of VPA was not detected. VPA-G was transferred more slowly. After 6 hr of dual recirculation, equilibrium had not been reached and VPA-G had undergone extensive hydrolysis to VPA (34%) and rearrangement via acyl migration to structural isomers (collectively VPA-GR, 9%). Hydrolysis of VPA-G occurred, at least in part, in the perfusates contaminated with placental blood and/or with enzymes leached from placental tissue. Reliable transfer data for VPA-G were obtained using the dual single pass perfusion method. Steady state was achieved within 15 min and VPA, VPA-G and VPA-GR were transferred from maternal to fetal perfusates at 95, 13 and 17%, respectively, of antipyrine clearance. Transfer was positively correlated with lipophilicity as measured by the logarithm of the octanol/water partition coefficient: 0.204, -1.85, -1.66 for VPA, VPA-G and VPA-GR, respectively.

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@article{Fowler1989TransplacentalTA, title={Transplacental transfer and biotransformation studies of valproic acid and its glucuronide(s) in the perfused human placenta.}, author={David W. Fowler and Mervyn J. Eadie and Ronald G Dickinson}, journal={The Journal of pharmacology and experimental therapeutics}, year={1989}, volume={249 1}, pages={318-23} }