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Proton Gradient-Dependent Transport of Valproic Acid in Human Placental Brush-Border Membrane Vesicles

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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.

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Authors and Affiliations

  1. Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Hiroaki Nakamura, Fumihiko Ushigome, Noriko Koyabu, Kiyomi Tsukimori, Hitoo Nakano, Hisakazu Ohtani & Yasufumi Sawada

  2. Department of Reproduction and Gynecology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Shoji Satoh

Authors
  1. Hiroaki Nakamura
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  2. Fumihiko Ushigome
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  3. Noriko Koyabu
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Correspondence to Yasufumi Sawada.

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Nakamura, H., Ushigome, F., Koyabu, N. et al. Proton Gradient-Dependent Transport of Valproic Acid in Human Placental Brush-Border Membrane Vesicles. Pharm Res 19, 154–161 (2002). https://doi.org/10.1023/A:1014242931475

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