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

H. Nakamura, F. Ushigome, N. Koyabu, S. Satoh, K. Tsukimori, H. Nakano, H. Ohtani, Y. Sawada

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 [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, α-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. 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 [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.

Original languageEnglish
Pages (from-to)154-161
Number of pages8
JournalPharmaceutical research
Volume19
Issue number2
DOIs
Publication statusPublished - 2002 Mar 4
Externally publishedYes

Keywords

  • Human placenta
  • Lactic acid
  • Transport mechanism
  • Valproic acid

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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  • Cite this

    Nakamura, H., Ushigome, F., Koyabu, N., Satoh, S., Tsukimori, K., Nakano, H., Ohtani, H., & Sawada, Y. (2002). Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles. Pharmaceutical research, 19(2), 154-161. https://doi.org/10.1023/A:1014242931475