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 language | English |
|---|---|
| Pages (from-to) | 154-161 |
| Number of pages | 8 |
| Journal | Pharmaceutical Research |
| Volume | 19 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2002 |
| Externally published | Yes |
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Keywords
- Human placenta
- Lactic acid
- Transport mechanism
- Valproic acid
ASJC Scopus subject areas
- Chemistry(all)
- Pharmaceutical Science
- Pharmacology
Cite this
Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles. / Nakamura, H.; Ushigome, F.; Koyabu, N.; Satoh, S.; Tsukimori, K.; Nakano, H.; Ohtani, Hisakazu; Sawada, Y.
In: Pharmaceutical Research, Vol. 19, No. 2, 2002, p. 154-161.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles
AU - Nakamura, H.
AU - Ushigome, F.
AU - Koyabu, N.
AU - Satoh, S.
AU - Tsukimori, K.
AU - Nakano, H.
AU - Ohtani, Hisakazu
AU - Sawada, Y.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Human placenta
KW - Lactic acid
KW - Transport mechanism
KW - Valproic acid
UR - http://www.scopus.com/inward/record.url?scp=0036181726&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036181726&partnerID=8YFLogxK
U2 - 10.1023/A:1014242931475
DO - 10.1023/A:1014242931475
M3 - Article
C2 - 11883642
AN - SCOPUS:0036181726
VL - 19
SP - 154
EP - 161
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 2
ER -