Desenvolvimento e validação de um novo modelo de permeabilidade intestinal ex vivo em segmentos de jejuno de ratos para screening de novas moléculas

• Autor(a) principal: Silva, Laís Cristina da
• Data de Publicação: 2014
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• dARK ID: ark:/38995/00130000098h0
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/4379
• topic: Modelo ex vivo; Integridade da membrana; Permeabilidade aparente; TEER; Apparent permeability; Ex vivo model; Membrane integrity; MEDICINA::ANATOMIA PATOLOGICA E PATOLOGIA CLINICA

The main predictive models of absorption of potential new drugs in preclinical stage are focused on the gastrointestinal mucosa, given the predominance of this pathway in drug administration. Often, the fraction absorbed (Fa) can be predicted in ex vivo models (p.e. Ussing chambers), in vitro (p.e. Caco-2 cells monolayers), intestinal perfusion studies in situ and in vivo absorption. In the present study, from an adaptation of Snapwell ™ inserts, a new ex vivo model to evaluate the permeability of substances passively absorbed is proposed. High permeable drugs (metoprolol, caffeine and theophylline) and low permeable drugs (atenolol, ranitidine and cimetidine) were maintained in an incubator at 37 ° C under constant stirring (60 rpm) and carbogenic atmosphere (5% CO2). The viability of the jejunal membrane (52 Ω.cm2 ± 8.0) was observed remaining above 20 Ω.cm2 for 120 min incubation, under all conditions evaluated, including the addition of co-solvents (1% DMSO and 1% EtOH). Values of apparent permeability coefficients obtained (Papp) were characteristic of ex vivo permeation studies (3.8 to 12.6 x10-6 cm / s). Strong correlation was observed between the data obtained here versus data intestinal perfusion in vivo (r = 0.89), as well as the fraction absorbed in humans (r = 0.85), reported in the literature. Additionally, the model features high sensitivity and accuracy compared to other commonly used models in classification permeability of substances. In line, we can infer that the MTSSNAPWELL model demonstrates, yet, potential application in studies of screening for selection of low molecular weight, such as potential phytochemicals, as well as their synthetic analogues evaluated with low amount of sample (ca 10 mg).