Mangas-Sanjuan,V.(1), Gundogdu, E.(2), Navarro-Fontestad, C.(3), Gonzalez-Alvarez, I.(1), Bermejo, M.(1), Casabo, VG.(3)
(1) Departmento de IngenierÃa, Universidad Miguel Hernández de Elche; (2)Department of Biopharmaceutics and Pharmacokinetics, Ege University; (3)Departamento de Farmacia y TecnologÃa Farmacéutica, Universidad de Valencia.
Objectives: Fexofenadine HCl (FEX), a second generation non-sedating histamine H1 receptor antagonist, is an active metabolite of terfenadine. Oral formulations at a dose of 60-120 mg/day are available for FEX. Permeability of FEX was determined in an in vitro cell model at different donor concentrations, and the effect of sodium dodecyl sulfate (SDS) at two concentration levels (10 and 50 µM) on FEX permeability was evaluated.
Methods: The in vitro transport studies were developed in Caco-2 cell in apical-to-basolateral (AB) and basolateral-to-apical (BA) direction. Permeability values were estimated by non-linear regression of cumulative amounts in the receptor chamber, and remaining amounts in donor chamber versus time. The basic kinetic model comprises three compartments, donor, cell and acceptor chamber. The fitting procedures were performed using NONMEM 7.2 software with the first order conditional estimation method (FOCE) for objective function estimation and ADVAN9 subroutine. Several kinetic models were fitted to the data, functional and mechanistic models, selecting the best model with lowest objective function value. The inter-individual and residual variabilities of the kinetic parameters were described with the use of exponential models. Goodness of fit plots and visual predictive check were generated in the aim of confirm the final model.
Results:The analysis of A-B and B-A permeabilities suggested the existence of an efflux mechanism. The best model fit corresponded to a kinetic model with passive mechanism and an efflux carrier located at the apical side of the enterocite. The presence of high concentration of surfactant (50 mM) affects to the passive diffusion of FEX differently for each direction of transport. Permeability as a function of time and Tlag parameters were used to account for the intercept of the cumulative fractions permeated versus time that was different from 0.
Conclusions:Fexofenadine has a low intestinal permeability in vitro in Caco-2 cells and the transport of the drug is concentration-dependent due to the involvement of Pgp. The three compartment modeling based on differential equations improved the basic approach for parameter estimation (fitting permeabilities versus donor concentration) as it allow to characterize apical and basolateral membrane permeabilities, beside having the advantage of its broader applicability i.e with non sink conditions and time dependent permeability.
References
[1]. Gundogdu E, Mangas-Sanjuan V, Gonzalez-Alvarez I, Bermejo M, Karasulu E. In vitro-in situ permeability and dissolution of fexofenadine with kinetic modeling in the presence of sodium dodecyl sulfate. Eur J Drug Metab Pharmacokinet. 2011 Aug 11.
[2]. Gonzalez-Alvarez I, Fernandez-Teruel C, Garrigues TM, Casabo VG,Ruiz-Garcia A, Bermejo M (2005) Kinetic modeling of passivetransport and active efflux of a fluoroquinolone across Caco-2 cells using a compartmental approach in NONMEM. Xenobiotica35(12):1067-1088
[3]. Tavelin, S., J. Grasjo, et al. (2002). “Applications of epithelial cell culture in studies of drug transport.” Methods Mol Biol 188: 233-272.
Reference: PAGE 21 (2012) Abstr 2322 [www.page-meeting.org/?abstract=2322]
Poster: Other Modelling Applications