title: Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles.
abstract: OBJECTIVE
  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 [3H]valproic acid and [14C]lactic acid was measured by using human placental brush-border membrane vesicles.
  
  
  RESULTS
  The uptakes of [3H]valproic acid and [14C]lactic acid into brush-border membrane vesicles were greatly stimulated at acidic extravesicular pH. The uptakes of [3H]valproic acid and [14C]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 [3H]valproic acid and [14C]lactic acid, respectively. Furthermore, lactic acid competitively inhibited [3H]valproic acid uptake and vice versa.
  
  
  CONCLUSIONS
  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 [3H]valproic acid and [14C]lactic acid, suggesting that other transport systems may also contribute to the elevated fetal blood concentration of valproic acid in gravida.
authors.affiliation: Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ushigome
authors.forename: Noriko
authors.initials: N
authors.lastname: Koyabu
authors.forename: Shoji
authors.initials: S
authors.lastname: Satoh
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Tsukimori
authors.forename: Hitoo
authors.initials: H
authors.lastname: Nakano
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D000328:Adult; D000465:Algorithms; D000927:Anticonvulsants / Q000378:metabolism*; D001693:Biological Transport, Active; D005227:Fatty Acids / Q000494:pharmacology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D015203:Reproducibility of Results; D014635:Valproic Acid / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D005227:Fatty Acids; D019344:Lactic Acid; D014635:Valproic Acid