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Antimicrobial Agents and Chemotherapy, March 2003, p. 1047-1051, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1047-1051.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Influence of P-Glycoprotein Inhibitors on Accumulation of Macrolides in J774 Murine Macrophages

Cristina Seral, Jean-Michel Michot, Hugues Chanteux, Marie-Paule Mingeot-Leclercq, Paul M. Tulkens, and Françoise Van Bambeke*

Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Brussels, Belgium

Received 4 April 2002/ Returned for modification 27 August 2002/ Accepted 25 November 2002

The influence of inhibitors of P-glycoprotein (verapamil [VE], cyclosporine [CY], and GF120918 [GF]) on the cell handling of macrolides (erythromycin [ERY], clarithromycin [CLR], roxithromycin [ROX], azithromycin [AZM], and telithromycin [TEL]) was examined in J774 murine macrophages. The net influx rates of AZM and TEL were increased from 2- to 3.5-fold in the presence of these inhibitors, but their efflux was slowed only marginally. At 3 h, the inhibitors increased the levels of AZM, ERY, and TEL accumulation approximately three- to fourfold (the effect of VE, however, was lower) but did not influence CLR accumulation (the inhibitors had an intermediate behavior on ROX accumulation). The effect was concentration dependent (half-maximal increases in the level of accumulation of AZM were obtained with GF, CY, and VE at 0.5, 5, and 10 µM, respectively). ATP depletion also caused an approximately threefold increase in the level of accumulation of AZM. Two inhibitors of MRP (probenecid [2.5 mM] and gemfibrozil [0.25 mM]) had no effect. Monensin (a proton ionophore) completely suppressed the accumulation of AZM in control cells as well as in cells incubated in the presence of VE, demonstrating that transmembrane proton gradients are the driving force causing the accumulation of AZM in both cases. Yet, VE did not alter the pH of the lysosomes (approximately 5) or of the cytosol (approximately 7.1). P-glycoprotein was detected by immunostaining at the cell surface as well as in intracellular vacuoles (endosomes and lysosomes). The data suggest that the influx of AZM, ERY, TEL, and ROX is adversely influenced by the activity of P-glycoprotein in J774 macrophages, resulting in suboptimal drug accumulation.

* Corresponding author. Mailing address: Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 73.70 Avenue E. Mounier 73, B-1200 Brussels, Belgium. Phone: 32-2-7647378. Fax: 32-2-7647373. E-mail: vanbambeke{at}facm.ucl.ac.be.

Antimicrobial Agents and Chemotherapy, March 2003, p. 1047-1051, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1047-1051.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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