Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles

Purpose. To investigate the transport mechanism of valproic acid across the human placenta, we used human placental brush-border membrane vesicles and compared them with that of lactic acid. Methods. Transport of [H-3]valproic acid and [C-14]lactic acid was measured by using human placental brush-border membrane vesicles. Results. The uptakes of [H-3]valproic acid and [C-14]lactic acid into brush-border membrane vesicles were greatly stimulated at acidic extravesicular pH. The uptakes of [H-3]valproic acid and [C-14]lactic acid were inhibited by various fatty acids, p-chloromercuribenzene sulfonate, alpha-cyano-4-hydroxycinnamate, and FCCP. A kinetic analysis showed that it was saturable, with Michaelis constants (Kt) of 1.04+/-0.41 mM and 1.71+/-0.33 mM for [H-3]valproic acid and [C-14]lactic acid. respectively. Furthermore, lactic acid competitively inhibited [3H]valproic acid uptake and vice versa. Conclusion. These results suggest that the transport of valproic acid across the microvillous membrane of human placenta is mediated by a proton-linked transport system that also transports lactic acid, However, some inhibitors differentially inhibited the uptakes of [H-3]valproic acid and [C-14]lactic acid, suggesting that other transport systems may also contribute to the elevated fetal blood concentration of valproic acid in gravida.