Transplacental transfer and biotransformation studies of valproic acid and its glucuronide(s) in the perfused human placenta.
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.
Fowler
D W
DW
Department of Medicine University of Queensland, Royal Brisbane Hospital, Australia.
Eadie
M J
MJ
Dickinson
R G
RG
D001711:Biotransformation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008657:Metabolic Clearance Rate; D010477:Perfusion; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012995:Solubility; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
C041285:valproic acid glucuronide; D014635:Valproic Acid