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Antimicrobial Agents and Chemotherapy, July 2004, p. 2673-2682, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2673-2682.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Active Efflux of Ciprofloxacin from J774 Macrophages through an MRP-Like Transporter

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

Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, B-1200 Brussels, Belgium

Received 11 November 2003/ Returned for modification 17 February 2004/ Accepted 1 March 2004

The accumulation and efflux kinetics of ciprofloxacin have been examined by using murine J774 macrophages. Accumulation (at equilibrium) was increased (three- to fourfold) (i) when cells were incubated with high extracellular drug concentrations (typically 200 mg/liter) as opposed to clinically meaningful concentrations (10 mg/liter or lower), (ii) during ATP- depletion and at acid pH, and (iii) during coincubation with probenecid, gemfibrozil and the preferential multidrug resistance-related protein (MRP) inhibitor MK571. All these conditions were also associated with a marked decrease in ciprofloxacin efflux (half-lives increased from <2 min in controls to up to 10 min). Monensin (a proton ionophore), verapamil, and the preferential P-glycoprotein (P-gp) inhibitor GF120918 had no or only minimal effect, while cyclosporin A, which is not specific for P-gp but also acts on MRP, had an intermediate effect. Short-term uptake studies showed that the influence of the modulators on the apparent drug influx was almost immediate (delay of ≤1 min). Cells made resistant to probenecid and showing a marked overexpression of MRP1 (by Western blot analysis and confocal microscopy) accumulated ciprofloxacin to almost the same extent as did control cells, but efflux was inhibited less by probenecid, gemfibrozil, and MK571. We conclude that ciprofloxacin is subject to constitutive efflux in J774 macrophages through the activity of an MRP-related transporter which is probably distinct from MRP1. We also suggest that the cellular accumulation of ciprofloxacin in wild-type cells is constitutively impaired at therapeutically meaningful concentrations.

* Corresponding author. Mailing address: UCL 7370 Ave. E. Mounier 73 B-1200 Brussels, Belgium. Phone: 32-2-762.21.36. Fax: 32-2-764.73.73. E-mail: tulkens{at}facm.ucl.ac.be.

Antimicrobial Agents and Chemotherapy, July 2004, p. 2673-2682, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2673-2682.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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