Abstract
The aim of the present study was to characterize the mechanism of erythromycin transport at the blood-placenta barrier, using TR-TBT 18d-1 cells as a model of rat syncytiotrophoblasts. [14C]Erythromycin was taken up by TR-TBT 18d-1 cells with a Michaelis constant of 466 μM. Although the uptake was not dependent on extracellular Na+ or Cl-, it was increased at weakly alkaline pH. Significant overshoot of [ 14C]erythromycin uptake by placental brush-border membrane vesicles was observed in the presence of an outwardly directed proton gradient. These results indicate that erythromycin is transferred by the H+-coupled transport system in syncytiotrophoblasts. To address the physiological transport of erythromycin in rat placenta, fetal-to-maternal transport clearance was estimated by means of the single placental perfusion technique. Clearance of [14C]erythromycin was higher than that of [14C]inulin, a paracellular pathway marker, and was decreased by the addition of 5 mM erythromycin, indicating that saturable efflux system from fetus to mother is involved. The effect of various transporter inhibitors on [14C] erythromycin efflux from TR-TBT 18d-1 cells was evaluated. cyclosporin A, fumitremorgin C, and probenecid had no effect, whereas ethylisopropylamiloride, a specific inhibitor of Na+/H+ exchangers (NHEs), was significantly inhibitory. These results suggest that erythromycin efflux transport at the rat blood-placenta barrier is mediated by an erythromycin/H+ antiport system, driven by H+ supplied by NHEs.
| Original language | English |
|---|---|
| Pages (from-to) | 1576-1581 |
| Number of pages | 6 |
| Journal | Drug Metabolism and Disposition |
| Volume | 38 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2010 Sep |
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ASJC Scopus subject areas
- Pharmacology
- Pharmaceutical Science
Cite this
Proton-coupled erythromycin antiport at rat blood-placenta barrier. / Sai, Yoshimichi; Nishimura, Tomohiro; Ochi, Kaori; Tanaka, Noriaki; Takagi, Akinori; Tomi, Masatoshi; Kose, Noriko; Kobayashi, Yasuna; Miyakoshi, Naoki; Kitagaki, Shinji; Mukai, Chisato; Nakashima, Emi.
In: Drug Metabolism and Disposition, Vol. 38, No. 9, 09.2010, p. 1576-1581.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Proton-coupled erythromycin antiport at rat blood-placenta barrier
AU - Sai, Yoshimichi
AU - Nishimura, Tomohiro
AU - Ochi, Kaori
AU - Tanaka, Noriaki
AU - Takagi, Akinori
AU - Tomi, Masatoshi
AU - Kose, Noriko
AU - Kobayashi, Yasuna
AU - Miyakoshi, Naoki
AU - Kitagaki, Shinji
AU - Mukai, Chisato
AU - Nakashima, Emi
PY - 2010/9
Y1 - 2010/9
N2 - The aim of the present study was to characterize the mechanism of erythromycin transport at the blood-placenta barrier, using TR-TBT 18d-1 cells as a model of rat syncytiotrophoblasts. [14C]Erythromycin was taken up by TR-TBT 18d-1 cells with a Michaelis constant of 466 μM. Although the uptake was not dependent on extracellular Na+ or Cl-, it was increased at weakly alkaline pH. Significant overshoot of [ 14C]erythromycin uptake by placental brush-border membrane vesicles was observed in the presence of an outwardly directed proton gradient. These results indicate that erythromycin is transferred by the H+-coupled transport system in syncytiotrophoblasts. To address the physiological transport of erythromycin in rat placenta, fetal-to-maternal transport clearance was estimated by means of the single placental perfusion technique. Clearance of [14C]erythromycin was higher than that of [14C]inulin, a paracellular pathway marker, and was decreased by the addition of 5 mM erythromycin, indicating that saturable efflux system from fetus to mother is involved. The effect of various transporter inhibitors on [14C] erythromycin efflux from TR-TBT 18d-1 cells was evaluated. cyclosporin A, fumitremorgin C, and probenecid had no effect, whereas ethylisopropylamiloride, a specific inhibitor of Na+/H+ exchangers (NHEs), was significantly inhibitory. These results suggest that erythromycin efflux transport at the rat blood-placenta barrier is mediated by an erythromycin/H+ antiport system, driven by H+ supplied by NHEs.
AB - The aim of the present study was to characterize the mechanism of erythromycin transport at the blood-placenta barrier, using TR-TBT 18d-1 cells as a model of rat syncytiotrophoblasts. [14C]Erythromycin was taken up by TR-TBT 18d-1 cells with a Michaelis constant of 466 μM. Although the uptake was not dependent on extracellular Na+ or Cl-, it was increased at weakly alkaline pH. Significant overshoot of [ 14C]erythromycin uptake by placental brush-border membrane vesicles was observed in the presence of an outwardly directed proton gradient. These results indicate that erythromycin is transferred by the H+-coupled transport system in syncytiotrophoblasts. To address the physiological transport of erythromycin in rat placenta, fetal-to-maternal transport clearance was estimated by means of the single placental perfusion technique. Clearance of [14C]erythromycin was higher than that of [14C]inulin, a paracellular pathway marker, and was decreased by the addition of 5 mM erythromycin, indicating that saturable efflux system from fetus to mother is involved. The effect of various transporter inhibitors on [14C] erythromycin efflux from TR-TBT 18d-1 cells was evaluated. cyclosporin A, fumitremorgin C, and probenecid had no effect, whereas ethylisopropylamiloride, a specific inhibitor of Na+/H+ exchangers (NHEs), was significantly inhibitory. These results suggest that erythromycin efflux transport at the rat blood-placenta barrier is mediated by an erythromycin/H+ antiport system, driven by H+ supplied by NHEs.
UR - http://www.scopus.com/inward/record.url?scp=77955989821&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955989821&partnerID=8YFLogxK
U2 - 10.1124/dmd.110.033266
DO - 10.1124/dmd.110.033266
M3 - Article
C2 - 20566696
AN - SCOPUS:77955989821
VL - 38
SP - 1576
EP - 1581
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 9
ER -