Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier 73 bte B1.73.05, B-1200 Brussels, Belgium.
Int J Antimicrob Agents. 2011 Sep;38(3):249-56. doi: 10.1016/j.ijantimicag.2011.05.011. Epub 2011 Jul 20.
Fluoroquinolones enter eukaryotic cells but the correlation between cellular accumulation and activity remains poorly established. Gemifloxacin is known to accumulate to a larger extent than most other fluoroquinolones in tissues. Using murine J774 macrophages and human THP-1 monocytes, we show that gemifloxacin accumulates more than ciprofloxacin and even moxifloxacin. Whilst showing indistinguishable kinetics of accumulation in J774 macrophages, gemifloxacin was released at an approximately two-fold slower rate than ciprofloxacin and its release was only partial. Gemifloxacin was also a weaker substrate than ciprofloxacin for the efflux transporter Mrp4 active in J774 macrophages. In cells infected with Listeria monocytogenes or Staphylococcus aureus (typical cytoplasmic and phagolysosomal organisms, respectively), gemifloxacin was equipotent to moxifloxacin and ciprofloxacin in concentration-dependent experiments if data are normalised based on the minimum inhibitory concentration (MIC) in broth. Thus, larger cellular concentrations of gemifloxacin than of moxifloxacin or ciprofloxacin were needed to obtain a similar target effect. Fractionation studies showed a similar subcellular distribution for all three fluoroquinolones, with approximately two-thirds of the cell-associated drug recovered in the soluble fraction (cytosol). These data suggest that cellular accumulation of fluoroquinolones is largely a self-defeating process as far as activity is concerned, with the intracellular drug made inactive in proportion to its accumulation level. Whilst these observations do not decrease the intrinsic value of fluoroquinolones for the treatment of intracellular infections, they indicate that ranking fluoroquinolones based on cell accumulation data without measuring the corresponding intracellular activity may lead to incorrect conclusions regarding their real potential.
氟喹诺酮类药物可以进入真核细胞，但细胞内积累与活性之间的相关性仍未得到充分证实。加替沙星在组织中的积累程度大于大多数其他氟喹诺酮类药物。本研究使用鼠源 J774 巨噬细胞和人 THP-1 单核细胞，证明加替沙星比环丙沙星甚至莫西沙星积累得更多。尽管在 J774 巨噬细胞中积累的动力学相似，但加替沙星的释放速度比环丙沙星慢约两倍，且释放不完全。加替沙星也是 J774 巨噬细胞中活性的外排转运蛋白 Mrp4 的弱底物。在感染李斯特菌或金黄色葡萄球菌（分别为典型的细胞质和吞噬溶酶体病原体）的细胞中，如果根据肉汤中的最低抑菌浓度（MIC）对数据进行归一化，加替沙星在浓度依赖性实验中与莫西沙星和环丙沙星等效。因此，与莫西沙星或环丙沙星相比，需要更高的细胞内加替沙星浓度才能达到相似的靶效应。分级研究表明，所有三种氟喹诺酮类药物的亚细胞分布相似，约三分之二的细胞结合药物存在于可溶部分（胞质溶胶）。这些数据表明，就活性而言，氟喹诺酮类药物的细胞内积累在很大程度上是一种适得其反的过程，随着药物积累水平的增加，细胞内药物的活性会降低。尽管这些观察结果并没有降低氟喹诺酮类药物治疗细胞内感染的固有价值，但它们表明，在不测量相应的细胞内活性的情况下，根据细胞积累数据对氟喹诺酮类药物进行排序可能会导致对其实际潜力的错误结论。
