Kinetic characterization of secretory transport of a new ciprofloxacin derivative (CNV97100) across Caco-2 cell monolayers.

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 < 0.05) than that of ciprofloxacin. The absorptive permeabilities (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 approximately 1). The transport of compounds without 4'-N-substitution (i.e., ciprofloxacin and CNV97100) favored secretion (efflux ratio approximately 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 x cm(-2) x 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 microM) and cyclosporin A (CsA, 20 microM) significantly (p < 0.05) inhibited P(BA) but significantly (p < 0.05) enhanced P(AB). Multidrug resistance related protein (MRP) inhibitor leukotriene C(4) only decreased (p < 0.05) 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 < 0.05), with an IC(90) value of 96.5 microM. 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. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2511-2519, 2002