title: Mathematical modelling of in situ and in vitro efflux of ciprofloxacin and grepafloxacin.
abstract: The efflux process due to p-glycoprotein-like mechanisms of ciprofloxacin (CIP) and grepafloxacin (GRX) has been studied "in situ" in rats and "in vitro" in Caco-2 cells. The results were modelled by a curve fitting procedure which allowed the characterization of the passive (Pd) and carrier mediated parameters (Vm and Km) from the raw data without initial velocities estimation. CIP absorption in rat was characterized as a passive diffusion at the assayed concentrations. Although the involvement of an efflux transporter cannot be ruled out, its relevance in the transport of the fluoroquinolone is negligible. In GRX absorption, an efflux process is implicated and it is detected in both absorption models. GRX permeability depends on the intestinal segment, reflecting the previously reported different expression level of the efflux transporters along the gut in rat. A first attempt to correlate the "in vitro" and the "in situ" data has been done. The mathematical model has been constructed using very simplistic assumptions and it will require further refinement but, nevertheless, the results are promising and demonstrate that a good modelling approach helps to identify the system critical parameters and how the system behaviour change when the parameters are modified as it happens when we move from the "in vitro" to the "in situ" level. Predicted versus experimental permeability values show a good correlation, demonstrating that the relevance of the secretion process "in situ" in rat can be predicted from the "in vitro" cell results.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Valencia, Av. Vicente A. Estellés sn Burjassot, 46100 Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Rodríguez-Ibáñez
authors.forename: G
authors.initials: G
authors.lastname: Sánchez-Castaño
authors.forename: M
authors.initials: M
authors.lastname: Montalar-Montero
authors.forename: T M
authors.initials: TM
authors.lastname: Garrigues
authors.forename: M
authors.initials: M
authors.lastname: Bermejo
authors.forename: V
authors.initials: V
authors.lastname: Merino
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002939:Ciprofloxacin / Q000493:pharmacokinetics*; D004058:Diffusion; D024841:Fluoroquinolones / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D010477:Perfusion / Q000379:methods; D010879:Piperazines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D010879:Piperazines; D002939:Ciprofloxacin; C075375:grepafloxacin