Desenvolvimento e validação de um novo modelo de permeabilidade intestinal ex vivo em segmentos de jejuno de ratos para screening de novas moléculas
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2014-09-29
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Universidade Federal de Goiás
Resumo
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).
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SILVA, L. C. Desenvolvimento e validação de um novo modelo de permeabilidade intestinal ex vivo em segmentos de jejuno de ratos para screening de novas moléculas. 2014. 86 f. Dissertação (Mestrado em Ciências da Saúde) - Universidade Federal de Goiás, Goiânia, 2014.