title: 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 < 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164-6534, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-García
authors.forename: Huimin
authors.initials: H
authors.lastname: Lin
authors.forename: José M
authors.initials: JM
authors.lastname: Plá-Delfina
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001693:Biological Transport, Active / Q000502:physiology; D018938:Caco-2 Cells / Q000378:metabolism*; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D010599:Pharmacokinetics
chemical_list: C587765:3,4-dimethylciprofloxacin; D000890:Anti-Infective Agents; C473955:CNV9710; D026901:Membrane Transport Proteins; D002939:Ciprofloxacin