P-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model
AbstractP-Glycoprotein-Mediated Transport of Moxifloxacin in a Calu-3 Lung Epithelial Cell Model ▿ Julien Brillault 1 , 2 , Whocely Victor De Castro 1 , 2 , Thomas Harnois 3 , Alain Kitzis 2 , 3 , 4 , Jean-Christophe Olivier 1 , 2 and William Couet 1 , 2 , 4 , * 1 INSERM, ERI-23, 40 Avenue du Recteur Pineau, Poitiers, France 2 Université de Poitiers, UFR Médecine-Pharmacie, 6 Rue de la Milétrie, Poitiers, France 3 Institut de Physiologie et de Biologie Cellulaire, CNRS UMR6187, Université de Poitiers, Poitiers, France 4 CHU Poitiers, 2 Rue de la Milétrie, Poitiers, France ABSTRACT Moxifloxacin (MXF) is a fluoroquinolone antibiotic that is effective against respiratory infections. However, the mechanisms of MXF lung diffusion are unknown. Active transport in other tissues has been suggested for several members of the fluoroquinolone family. In this study, transport of MXF was systematically investigated across a Calu-3 lung epithelial cell model. MXF showed polarized transport, with the secretory permeability being twice as high as the absorptive permeability. The secretory permeability was concentration dependent (apparent P max = 13.6 × 10 −6 cm·s −1 ; apparent K m = 147 μM), suggesting saturated transport at concentrations higher than 350 μg/ml. The P-glycoprotein inhibitor PSC-833 inhibited MXF transport in both directions, whereas probenecid, a multidrug resistance-related protein inhibitor, appeared to have no effect in the Calu-3 model. Moreover, rifampin, a known inducer of efflux transport proteins, upregulated the expression of P-glycoprotein in Calu-3 cells and enhanced MXF active transport. In conclusion, this study clearly indicates that MXF is subject to P-glycoprotein-mediated active transport in the Calu-3 model. This P-glycoprotein-dependent secretion may lead to higher MXF epithelial lining fluid concentrations than those in plasma. Furthermore, drug-drug interactions may be expected when MXF is combined with other P-glycoprotein substrates or modulators.