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Antimicrobial Agents and Chemotherapy, November 1999, p. 2710-2715, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Mechanisms of Fluoroquinolone Transport by Human Neutrophils

John D. Walters,1,2,* Fanjie Zhang,1 and Robin J. Nakkula1

Section of Periodontology, College of Dentistry,1 and Department of Medical Biochemistry, College of Medicine,2 The Ohio State University Health Sciences Center, Columbus, Ohio

Received 25 January 1999/Returned for modification 23 May 1999/Accepted 30 August 1999

Neutrophils accumulate ciprofloxacin and other fluoroquinolones, a process that enhances the killing of intracellular pathogens and could facilitate the delivery of these agents to infection sites by migrating neutrophils. The mechanisms by which transport occurs have not been characterized. In the present study, quiescent neutrophils transported ciprofloxacin with an observed Km of 167 µg/ml (501 µM) and a maximum velocity of 25.2 ng/min/106 cells. When neutrophils were stimulated with phorbol myristate acetate (PMA), a second component of ciprofloxacin transport was induced. This pathway had an apparent Km of 9.76 µg/ml (29.3 µM) and a maximum velocity of 59.3 ng/min/106 cells. Transport by both pathways was Na+ independent. Ciprofloxacin transport by quiescent cells was relatively insensitive to pH and N-ethylmaleimide but was competitively inhibited by adenine (Ki = 1.55 mM). Papaverine, a benzylisoquinoline known to inhibit nucleobase transport, also inhibited ciprofloxacin transport by quiescent cells. In contrast, transport by PMA-stimulated cells was enhanced at pH 8.2, inhibited at pH 6.2, and blocked by N-ethylmaleimide. Cationic and neutral amino acids and cystine competitively inhibited ciprofloxacin transport by PMA-stimulated neutrophils (Ki = 158 µM for ornithine) but had little effect on quiescent cells. PMA-activated transport was not inhibited when the Na+ in the medium was replaced with K+ or Li+, and the pattern of inhibition by cationic and neutral amino acids was similar. In summary, neutrophils continuously transport ciprofloxacin via a transport pathway shared by adenine. Activation by PMA induces a separate, higher-affinity transport pathway shared by a broad scope of amino acids. Neutrophils utilize one or both of these mechanisms to transport other fluoroquinolones.

* Corresponding author. Mailing address: College of Dentistry, The Ohio State University, 305 W. 12th Ave., Columbus, OH 43210. Phone: (614) 292-1322. Fax: (614) 292-2438. E-mail: walters.2{at}osu.edu.

Antimicrobial Agents and Chemotherapy, November 1999, p. 2710-2715, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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