PMID: 2496226Apr 1, 1989Paper

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

The Journal of Pharmacology and Experimental Therapeutics
D W FowlerR G Dickinson

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...Continue Reading

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