title: Kinetic modelling of the intestinal transport of sarafloxacin. Studies in situ in rat and in vitro in Caco-2 cells.
abstract: The absorption kinetics of sarafloxacin, as a model of fluoroquinolone structure, were studied in the rat small intestine and in Caco-2 cells. The objective of the study was to investigate the mechanistic basis of the drug's intestinal transport in comparison with other members of the fluoroquinolone family and to apply a mathematical modelling approach to the transport process. In the rat small intestine, sarafloxacin showed dual mechanisms of intestinal absorption with a passive diffusional component and an absorptive carrier-mediated component. The characteristics of the animal study design made it suitable for population analysis, thus allowing the accurate estimation of transport parameters and their inter and intra-individual variances. The transport system in the rat model was ATP-dependent, as sodium azide was able to decrease the absorption rate constant in a concentration-dependent fashion. The inhibition mechanism of sodium azide was modelled based on its ATP depletion capacity. The rationale of this approach was to consider the inhibitor-carrier interaction as a concentration- dependent response. This interaction was accurately described by a non-competitive mechanism. In Caco-2 cells, sarafloxacin showed a concentration dependent permeability in both directions apical to basal, and basal to apical. The permeability values and ratios of permeability values at different concentrations suggested the presence of two carriers (absorption and efflux carriers). The passive diffusion component in both systems was compared to that predicted by the absorption-partition correlation, previously established for two series of fluoroquinolones. The discrepancy between the experimental and predicted value suggested the presence of an efflux mechanism similar to that already described for other fluoroquinolones. The differences and similarities of the in situ and the in vitro results are discussed as well as the usefulness of the modelling approach.
authors.affiliation: Facultad de Farmacia, Departamento Farmacia y Tecnología Farmacéutica, Universidad de Valencia, España, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Fernandez-Teruel
authors.forename: I
authors.initials: I
authors.lastname: Gonzalez-Alvarez
authors.forename: V G
authors.initials: VG
authors.lastname: Casabó
authors.forename: A
authors.initials: A
authors.lastname: Ruiz-Garcia
authors.forename: M
authors.initials: M
authors.lastname: Bermejo
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000465:Algorithms; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D000963:Antimetabolites / Q000494:pharmacology; D001692:Biological Transport; D018938:Caco-2 Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004058:Diffusion; D004734:Energy Metabolism / Q000187:drug effects; D024841:Fluoroquinolones / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008297:Male; D015233:Models, Statistical; D010085:Oxidative Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D019810:Sodium Azide / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D000963:Antimetabolites; D024841:Fluoroquinolones; D008055:Lipids; D002939:Ciprofloxacin; D000255:Adenosine Triphosphate; D019810:Sodium Azide; C047224:sarafloxacin