1. Int J Antimicrob Agents. 2011 Sep;38(3):249-56. Epub 2011 Jul 20.

Cellular accumulation of fluoroquinolones is not predictive of their
intracellular activity: studies with gemifloxacin, moxifloxacin and ciprofloxacin
in a pharmacokinetic/pharmacodynamic model of uninfected and infected

Vallet CM, Marquez B, Ngabirano E, Lemaire S, Mingeot-Leclercq MP, Tulkens PM,
Van Bambeke F.

Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Avenue E. Mounier 73 bte B1.73.05, B-1200
Brussels, Belgium.

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.

PMID: 21764262  [PubMed - in process]