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Antimicrobial Agents and Chemotherapy, June 2005, p. 2429-2437, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2429-2437.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Influence of Efflux Transporters on the Accumulation and Efflux of Four Quinolones (Ciprofloxacin, Levofloxacin, Garenoxacin, and Moxifloxacin) in J774 Macrophages

Jean-Michel Michot,{dagger} Cristina Seral,{dagger},{ddagger} Françoise Van Bambeke, Marie-Paule Mingeot-Leclercq, and Paul M. Tulkens*

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

Received 11 September 2004/ Returned for modification 22 December 2004/ Accepted 31 January 2005

Ciprofloxacin is subject to efflux from J774 macrophages through a multidrug resistance-related protein-like transporter (J. M. Michot, F. Van Bambeke, M. P. Mingeot-Leclercq, and P. M. Tulkens, Antimicrob. Agents Chemother. 48:2673-2682, 2004). Here, we compare ciprofloxacin to levofloxacin, garenoxacin, and moxifloxacin for transport. At 4 mg/liter, an apparent steady state in accumulation was reached after 30 to 60 min for all quinolones but to quite different levels (approximately 3, 5, 10, and 16 fold). Accumulation of ciprofloxacin was increased (to about 16 to 20 fold) by ATP depletion, increase in extracellular concentration, and the addition of probenecid, gemfibrozil, or MK571 (but not verapamil or GF120918). These treatments did not affect the accumulation of moxifloxacin. Levofloxacin and garenoxacin showed an intermediate behavior. Efflux of ciprofloxacin was slowed down by probenecid (half-life, 7.2 versus 1.6 min). Moxifloxacin efflux was faster and unaffected by probenecid (half-lifes, 0.27 versus 0.33 min). Efflux of levofloxacin and garenoxacin was modestly decreased by probenecid (1.5 and 2.1 fold). Accumulation of 14C-labeled ciprofloxacin was increased by unlabeled ciprofloxacin and moxifloxacin, but moxifloxacin was two times less potent. Accumulation of moxifloxacin at 4°C was almost identical to that at 37°C, whereas that of ciprofloxacin was minimal (levofloxacin and garenoxacin showed intermediate behaviors). Cells subjected to thermal shock (56°C; 10 min) accumulated all quinolones at a similar level (16 to 23 fold). We conclude that moxifloxacin is apparently not subject to efflux from J774 macrophages, even though it can interact with the ciprofloxacin transporter. Levofloxacin and garenoxacin are partially effluxed. Data suggest that efflux plays an important role in the differential accumulation of quinolones by J774 macrophages.

* 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: 32-2-764 73 70. Fax: 32-2-764 73 73. E-mail: tulkens{at}facm.ucl.ac.be.

{dagger} These two authors contributed equally to this work.

{ddagger} Present address: Department of Clinical Microbiology, University Hospital "Lozano Blesa," Zaragoza, Spain.

Antimicrobial Agents and Chemotherapy, June 2005, p. 2429-2437, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2429-2437.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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