Proton-coupled erythromycin antiport at rat blood-placenta barrier.
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. [(14)C]Erythromycin was taken up by TR-TBT 18d-1 cells with a Michaelis constant of 466 microM. Although the uptake was not dependent on extracellular Na(+) or Cl(-), it was increased at weakly alkaline pH. Significant overshoot of [(14)C]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 [(14)C]erythromycin was higher than that of [(14)C]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 [(14)C]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.
Sai
Yoshimichi
Y
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
Nishimura
Tomohiro
T
Ochi
Kaori
K
Tanaka
Noriaki
N
Takagi
Akinori
A
Tomi
Masatoshi
M
Kose
Noriko
N
Kobayashi
Yasuna
Y
Miyakoshi
Naoki
N
Kitagaki
Shinji
S
Mukai
Chisato
C
Nakashima
Emi
E
D000818:Animals; D004917:Erythromycin / Q000493:pharmacokinetics*; D005260:Female; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011522:Protons; D051381:Rats
D011522:Protons; D004917:Erythromycin