This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vazifeh, D.
Right arrow Articles by Labro, M.-T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vazifeh, D.
Right arrow Articles by Labro, M.-T.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 1999, p. 246-252, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Mechanism Underlying Levofloxacin Uptake by Human Polymorphonuclear Neutrophils

Doina Vazifeh,1 André Bryskier,2 and Marie-Thérèse Labro1,*

INSERM U479, CHU X. Bichat-Claude Bernard, 75018 Paris,1 and Antiinfective Research Department, Hoechst Marion Roussel, Romainville Cedex,2 France

Received 19 June 1998/Returned for modification 25 October 1998/Accepted 9 November 1998

The mechanism of radiolabeled levofloxacin ([3H]levofloxacin) uptake by human polymorphonuclear neutrophils (PMNs) was investigated by a classical velocity centrifugation technique. PMNs were incubated with levofloxacin for 5 to 180 min under various conditions before centrifugation through an oil cushion. Radioactivity was measured in the cell pellet to determine the amount of cell-associated drug. The uptake of levofloxacin was moderate with a cellular concentration/extracellular concentration ratio of about 4 to 6. Levofloxacin accumulated in PMNs parallel to the extracellular concentration, without saturation, over the range of 2.5 to 200 mg/liter (linear regression analysis: r = 0.92; P < 0.001). The activation energy was low (36 ± 7.2 kJ/mol). Levofloxacin uptake was increased in Ca2+-depleted, EGTA-containing medium by approximately 33% (P = 0.022), while Ni2+, a Ca2+ channel inhibitor, inhibited it in a concentration-dependent manner, with the concentration that inhibited 50% of control uptake being approximately 2.65 mM. Verapamil (an L-type Ca2+ channel inhibitor) and other pharmacologic agents which modify Ca2+ homeostasis did not modify levofloxacin uptake. Interestingly, Ca2+ and Mg2+ inhibited levofloxacin uptake in a concentration-dependent manner. EGTA, Ni2+, and verapamil did not modify levofloxacin efflux; thapsigargin, a Ca2+ pool-releasing agent, modestly increased the intracellular retention of levofloxacin. In addition, contrary to other fluoroquinolones, probenecid at 1 to 10 mM did not modify either levofloxacin uptake or efflux. These data are consistent with a mechanism of passive accumulation of levofloxacin in PMNs. Extracellular Ca2+ and Mg2+ may influence the structural conformation of levofloxacin or the lipophilicity of PMN membranes, thus explaining their effect on levofloxacin uptake.

* Corresponding author. Mailing address: INSERM U479, CHU X. Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France. Phone: (33) 1 40 25 85 21. Fax: (33) 1 40 25 88 53. E-mail: labro{at}bichat.inserm.fr.

Antimicrobial Agents and Chemotherapy, February 1999, p. 246-252, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Nguyen, H. A., Grellet, J., Paillard, D., Dubois, V., Quentin, C., Saux, M.-C. (2006). Factors influencing the intracellular activity of fluoroquinolones: a study using levofloxacin in a Staphylococcus aureus THP-1 monocyte model. J Antimicrob Chemother 57: 883-890 [Abstract] [Full Text]  
  • Michot, J.-M., Seral, C., Van Bambeke, F., Mingeot-Leclercq, M.-P., Tulkens, P. M. (2005). Influence of Efflux Transporters on the Accumulation and Efflux of Four Quinolones (Ciprofloxacin, Levofloxacin, Garenoxacin, and Moxifloxacin) in J774 Macrophages. Antimicrob. Agents Chemother. 49: 2429-2437 [Abstract] [Full Text]  
  • Labro, M. T., Abdelghaffar, H., Babin-Chevaye, C. (2004). Interaction of the New Ketolide ABT-773 (Cethromycin) with Human Polymorphonuclear Neutrophils and the Phagocytic Cell Line PLB-985 In Vitro. Antimicrob. Agents Chemother. 48: 1096-1104 [Abstract] [Full Text]  
  • Niwa, M., Kanamori, Y., Hotta, K., Matsuno, H., Kozawa, O., Fujimoto, S., Uematsu, T. (2002). Priming by grepafloxacin on respiratory burst of human neutrophils: its possible mechanism. J Antimicrob Chemother 50: 469-478 [Abstract] [Full Text]  
  • Vazifeh, D., Abdelghaffar, H., Labro, M. T. (2002). Effect of Telithromycin (HMR 3647) on Polymorphonuclear Neutrophil Killing of Staphylococcus aureus in Comparison with Roxithromycin. Antimicrob. Agents Chemother. 46: 1364-1374 [Abstract] [Full Text]  
  • Abdelghaffar, H., Vazifeh, D., Labro, M. T. (2001). Cellular Uptake of Two Fluoroketolides, HMR 3562 and HMR 3787, by Human Polymorphonuclear Neutrophils In Vitro. Antimicrob. Agents Chemother. 45: 2798-2806 [Abstract] [Full Text]  
  • Edelstein, P. H., Shinzato, T., Doyle, E., Edelstein, M. A. C. (2001). In Vitro Activity of Gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and Its Pharmacokinetics in Guinea Pigs with L. pneumophila Pneumonia. Antimicrob. Agents Chemother. 45: 2204-2209 [Abstract] [Full Text]  
  • Labro, M.-T. (2000). Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or ""Immuno-Fairy Tales""?. Clin. Microbiol. Rev. 13: 615-650 [Abstract] [Full Text]  
  • Smith, R. P., Baltch, A. L., Franke, M. A., Michelsen, P. B., Bopp, L. H. (2000). Levofloxacin penetrates human monocytes and enhances intracellular killing of Staphylococcus aureus and Pseudomonas aeruginosa. J Antimicrob Chemother 45: 483-488 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»