Proton-coupled erythromycin antiport at rat blood-placenta barrier

Yoshimichi Sai, Tomohiro Nishimura, Kaori Ochi, Noriaki Tanaka, Akinori Takagi, Masatoshi Tomi, Noriko Kose, Yasuna Kobayashi, Naoki Miyakoshi, Shinji Kitagaki, Chisato Mukai, Emi Nakashima

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6 Citations (Scopus)

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 languageEnglish
Pages (from-to)1576-1581
Number of pages6
JournalDrug Metabolism and Disposition
Volume38
Issue number9
DOIs
Publication statusPublished - 2010 Sep

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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    Sai, Y., Nishimura, T., Ochi, K., Tanaka, N., Takagi, A., Tomi, M., Kose, N., Kobayashi, Y., Miyakoshi, N., Kitagaki, S., Mukai, C., & Nakashima, E. (2010). Proton-coupled erythromycin antiport at rat blood-placenta barrier. Drug Metabolism and Disposition, 38(9), 1576-1581. https://doi.org/10.1124/dmd.110.033266