Kinetic Characterization of Secretory Transport of a New Ciprofloxacin Derivative (CNV97100) across Caco-2 Cell Monolayers *

ABSTRACT: The kinetics of transport of a new fluoroquinolone antibiotic (CNV97100) and its analogs were characterized using the Caco-2 cell culture model. Unidirectional permeabilities of these analogs were greater ( p P AB ) of 4′- N -substituted analogs (CNV97101-104) were 400–600% greater, whereas the secretory permeability ( P BA ) was 25–80% greater than unsubstituted analogs because CNV97101-104 were poor substrates for efflux transporters (efflux ratio ≈ 1). The transport of compounds without 4′- N -substitution (i.e., ciprofloxacin and CNV97100) favored secretion (efflux ratio ≈ 4). Further characterization of CNV97100 transport revealed that it was concentration dependent (apparent K m  = 0.484 mM, and apparent V max  = 17.5 nmol · cm −2  · h −1 ), and temperature dependent ( E a  = 20.57 for P AB and 31.45 kcal/mol for P BA , respectively). p -Glycoprotein ( p -gp)inhibitors, such as verapamil (100 μM) and cyclosporin A (CsA, 20 μM) significantly ( p P BA but significantly ( p P AB . Multidrug resistance related protein (MRP) inhibitor leukotriene C 4 only decreased ( p P BA of ciprofloxacin but not that of CNV97100. In the presence of increasing concentrations of verapamil, the P BA of CNV97100 decreased significantly ( p 90 value of 96.5 μM. Taken together, these results suggested that 4′- N -alkylation of fluoroquinolones improves their absorptive permeability. Secretion of CNV97100 is dominated by p -gp, whereas the secretion of ciprofloxacin is via a combination of efflux transporters. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association