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.
Footnotes
This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology, Japan; the “High-Tech Research Center” and “Open Research Center” Project for Private Universities matching fund subsidy; and the Japan-Korea Basic Scientific Cooperation Program of the Japan Society for the Promotion of Science and Korea Science & Engineering Foundation.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033266.
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ABBREVIATIONS:
- P-gp
- P-glycoprotein
- MRP
- multidrug resistance protein
- ABC
- ATP-binding cassette
- SLC
- solute carrier
- Ko143
- [3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester]
- DMSO
- dimethyl sulfoxide
- BBMV
- brush-border membrane vesicle
- ALP
- alkaline phosphatase
- MES
- 4-morpholineethanesulfonic acid
- NHE
- Na+/H+ exchanger
- BCRP
- breast cancer resistance protein
- OAT
- organic anion transporter
- OSCP
- organic solute carrier protein
- OCTN1
- organic cation/ergothioneine transporter
- MATE
- multidrug and toxin extrusion.
- Received March 15, 2010.
- Accepted June 15, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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