title: Proton-coupled erythromycin antiport at rat blood-placenta barrier.
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. [(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.
authors.affiliation: Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishimura
authors.forename: Kaori
authors.initials: K
authors.lastname: Ochi
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Akinori
authors.initials: A
authors.lastname: Takagi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tomi
authors.forename: Noriko
authors.initials: N
authors.lastname: Kose
authors.forename: Yasuna
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyakoshi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kitagaki
authors.forename: Chisato
authors.initials: C
authors.lastname: Mukai
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima
mesh_terms: D000818:Animals; D004917:Erythromycin / Q000493:pharmacokinetics*; D005260:Female; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011522:Protons; D051381:Rats
chemical_list: D011522:Protons; D004917:Erythromycin