TY - JOUR T1 - Proton-Coupled Erythromycin Antiport at Rat Blood-Placenta Barrier JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1576 LP - 1581 DO - 10.1124/dmd.110.033266 VL - 38 IS - 9 AU - Yoshimichi Sai AU - Tomohiro Nishimura AU - Kaori Ochi AU - Noriaki Tanaka AU - Akinori Takagi AU - Masatoshi Tomi AU - Noriko Kose AU - Yasuna Kobayashi AU - Naoki Miyakoshi AU - Shinji Kitagaki AU - Chisato Mukai AU - Emi Nakashima Y1 - 2010/09/01 UR - http://dmd.aspetjournals.org/content/38/9/1576.abstract 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. ER -