1: Antimicrob Agents Chemother. 2006 May;50(5):1689-95. 

Cellular accumulation and activity of quinolones in ciprofloxacin-resistant j774

Michot JM, Heremans MF, Caceres NE, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke

Unite de Pharmacologie Cellulaire et Moleculaire, UCL 7370, avenue Mounier 73,
1200 Brussels, Belgium. vanbambeke@facm.ucl.ac.be.

Ciprofloxacin is the substrate for a multidrug resistance-related protein
(MRP)-like multidrug transporter in J774 mouse macrophages, which also modestly
affects levofloxacin but only marginally affects garenoxacin and moxifloxacin
(J.-M. Michot et al., Antimicrob. Agents Chemother. 49:2429-2437, 2005). Two
clones of ciprofloxacin-resistant cells were obtained by a stepwise increase in
drug concentration (from 34 to 51 to 68 mg/liter) in the culture fluid. Compared
to wild-type cells, ciprofloxacin-resistant cells showed (i) a markedly reduced
ciprofloxacin accumulation (12% of control) and (ii) a two- to threefold lower
sensitivity to the enhancing effect exerted by MRP-inhibitors (probenecid and
MK571) on ciprofloxacin accumulation or by ciprofloxacin itself. ATP-depletion
brought ciprofloxacin accumulation to similarly high levels in both wild-type
and ciprofloxacin-resistant cells. Garenoxacin and moxifloxacin accumulation
remained unaffected, and levofloxacin showed an intermediate behavior. DNA and
protein synthesis were not impaired in ciprofloxacin-resistant cells for
ciprofloxacin concentrations up to 100 mg/liter ( approximately 85 and 55%
inhibition, respectively, in wild-type cells). In Listeria
monocytogenes-infected ciprofloxacin-resistant cells, 12-fold higher
extracellular concentrations of ciprofloxacin were needed to show a
bacteriostatic effect in comparison with wild-type cells. The data suggest that
the resistance mechanism is mediated by an overexpression and/or increased
activity of the MRP-like ciprofloxacin transporter expressed at a basal level in
wild-type J774 macrophages, which modulates both the intracellular
pharmacokinetics and activity of ciprofloxacin.

PMID: 16641436 [PubMed - in process]