Quinolones are one of the largest classes of antimicrobial agents used worldwide. This review considers the quinolones that are available currently and used widely in Europe (norfoxacin, ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin) within their historical perspective, while trying to position them in the context of recent and possible future advances based on an understanding of: (1) their chemical structures and how these impact on activity and toxicity; (2) resistance mechanisms (mutations in target genes, efflux pumps); (3) their pharmacodynamic properties (AUC/MIC and Cmax/MIC ratios; mutant prevention concentration and mutant selection window); and (4) epidemiological considerations (risk of emergence of resistance, clonal spread). Their main indications are examined in relation to their advantages and drawbacks. Overall, it is concluded that these important agents should be used in an educated fashion, based on a careful balance between their ease of use and efficacy vs. the risk of emerging resistance and toxicity. However, there is now substantial evidence to support use of the most potent drug at the appropriate dose whenever this is required.
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][2674][2675][2676][2677][2678][2679][2680][2681][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 14 C-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.Fluoroquinolones have long been known to accumulate in phagocytic cells (8), but quite significant differences among closely related derivatives have been observed (3, 7, 13) which have so far not received satisfactory explanation. One factor that can modulate antibiotic accumulation in eucaryotic cells is their differential recognition by active efflux transporters (see reference 28 and the references cited therein). Fluoroquinolones are recognized by several eucaryotic multidrug transporters, most notably by two main members of the ATP-binding cassette superfamily, namely the multidrug resistance-related proteins (MRP) and the P-glycoprotein (28). In J774 macrophages, norfloxacin has been shown to be subject to efflux by a probenecid-and gemfibrozil-inhibitable transporter (2), which has been tentatively identified as a member of the MRP family (16). In this context, we have now examined the accumulation and efflux of levofloxacin and moxifloxacin in J774 macrophages in comparison with ciprofloxacin. These quinolones were chosen on the basis of their increasingly lipophilic character and potential clinic...
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.
The influence of inhibitors of P-glycoprotein (verapamil [VE], cyclosporine [CY], and GF120918 [GF]) on the cell handling of macrolides (erythromycin [ERY], clarithromycin [CLR], roxithromycin [ROX], azithromycin [AZM], and telithromycin [TEL]) was examined in J774 murine macrophages. The net influx rates of AZM and TEL were increased from 2-to 3.5-fold in the presence of these inhibitors, but their efflux was slowed only marginally. At 3 h, the inhibitors increased the levels of AZM, ERY, and TEL accumulation approximately three-to fourfold (the effect of VE, however, was lower) but did not influence CLR accumulation ( 1). P-glycoprotein was detected by immunostaining at the cell surface as well as in intracellular vacuoles (endosomes and lysosomes). The data suggest that the influx of AZM, ERY, TEL, and ROX is adversely influenced by the activity of P-glycoprotein in J774 macrophages, resulting in suboptimal drug accumulation.Active drug transporters have been described in both procaryotic and eucaryotic cells. Originally described as conferring resistance to anticancer agents in cancer cells, antibiotics in bacteria, or antifungal agents in fungi, these proteins appear today to be part of a very general mechanism that cells have developed to protect themselves from invasion by diffusible, foreign molecules (for a review, see reference 37). In this context, the occurrence of antibiotic transporters in eucaryotic cells has become a common observation (7, 33). More specifically, P-glycoprotein (also referred to as MDR1) and MRP, which are expressed in most cell types and which transport a large variety of drugs, have received much attention. These two types of transporters belong to the superfamily of ATP binding cassette transporters and use ATP hydrolysis as an energy source (28). They play a key role in drug disposition by modulating drug transport through epithelia and other biological barriers to an extent that was completely unsuspected only a few years ago (1).Focusing on macrolides, erythromycin has been shown to be transported by P-glycoprotein in Caco-2 intestinal cells (29, 34). In parallel, erythromycin and azithromycin are capable of inhibiting the transport of various substrates of the P-glycoprotein in epithelial cells in vitro as well as in vivo (9,12,13,23,30,31,39). Yet, little is known about the role of efflux transporters in the handling of macrolides by macrophages, in which these drugs are known to accumulate in large amounts (2,3,20,24).In the present study, we have examined directly in macrophages the potential influence of P-glycoprotein and MRP on the accumulation and efflux of five macrolides of clinical interest. We used both broad-spectrum, nonspecific inhibitors of P-glycoprotein (verapamil and cyclosporine) and MRP (probenecid and gemfibrozil) and the specific P-glycoprotein modulator GF120918 (11, 15). We selected the murine J774 murine macrophage line since much is already known about the dispositions of macrolides in these cells (2,3,36). MATERIALS AND METHODS Cells.We used J77...
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. Active efflux is a general means developed by cells for protection against invasion by amphiphilic, potentially harmful molecules (18). In this context, overexpression of multidrug efflux pumps is now recognized as a common and widespread mechanism of resistance to anticancer agents in eukaryotic cells (for a review, see reference 3). These pumps often display broad substrate specificities (7,15). It is therefore not surprising that they also transport other amphipathic drugs like antibiotics (for a review, see reference 19). In this context, we showed that the fluoroquinolone ciprofloxacin is subject to active efflux by a multidrug resistance-related protein (MRP)-like transporter in J774 mouse macrophages (11). The activity of this transporter significantly reduces the accumulation of ciprofloxacin in comparison with other drugs of the same class (10) and, as a consequence, impairs its activity against intracellular bacteria such as Listeria monocytogenes (13).-In an attempt to better characterize the transporter of ciprofloxacin, we have generated J774 macrophages with increased efflux capabilities toward this drug. We applied a procedure commonly used to select resistance to anticancer drugs (6), namely, the continuous exposure to progressively increasing concentrations of the drug under study. This methodology, which can select multifactorial resistance, is intended to mimic to some extent what may develop in vivo upon chronic exposure to the corresponding drug (6). We obtained stable cell lines resistant to 68 mg/liter (0.2 mM) ciprofloxacin. The present paper deals with a description of the quinolone pharmacokinetics and pharmacodynamics in these cells in comparison with the wild-type, parent cell line. MATERIALS AND METHODSCell culture and selection of ciprofloxacin-resistant J774 macrophages. All experiments were performed with J774 mouse macrophages. Wild-type cells were maintained exactly as reported previously (11). To select ciprofloxacinresistant cells, we used a stepwise approach similar to that described previously for obtaining probenecid-resistant J774 macrophages (1, 11). Based on preliminary experiments evaluating ciprofloxacin cytotoxicity in wild-type cells, a concentration of 34 mg/liter (0.1 mM) was used as a first selection step. After 4 weeks (i.e., up to passage 6), the ciprofloxacin concentration was increased to 51 mg/liter (0.15 mM) for 3 weeks (from passage 7 to 9) and then further increased to 68 mg/liter (0.2 mM) for 6 months (up to passage 30). At each increase in ciprofloxacin concentration, cells showed a marked but transient (1 to 2 passages) decrease in their multiplication rates, after which, however, they resumed at almost normal growth. Cells were then used for experiments up to the 120th passage, while being maintained in the continuous pr...
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