Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl–CoA by brain microsomal long-chain fatty acyl–CoA synthetases: relevance to bipolar disorder
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.