Determination of intestinal permeability using in situ perfusion model in rats : challenges and advantages to BCS classification applied to digoxin.
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2018
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Resumo
The purpose of this work was to describe the closed loop in situ perfusion method in rats and to compare the
difficulties and advantages with other methods proposed by regulatory agencies for BCS classification and finally
to illustrate its application to evaluate the permeability of digoxin at relevant clinical concentrations. Digoxin
was evaluated at two concentration levels: 1.0 μg/ml (with and without sodium azide 65.0 μg/ml) and 6.0 μg/
ml. These concentrations correspond to the ratio of the highest dose strength (0.25 mg) and the highest single
dose administered (1.5 mg) and the 250 ml of water. In situ closed loop perfusion studies in rats were performed
in the whole small intestine and also in duodenum, jejunum and ileum segments to evaluate the relevance of Pgp secretion in the overall permeability. A kinetic modelling approach involving passive permeation and efflux
transport mechanism allowed the estimation of the passive diffusional component and the Michaelis-menten
parameters. The estimated Km value demonstrated that at clinical luminal concentrations the efflux process is not
saturated and then it could be inhibited by other drugs, excipients or food components leading to the already
reported clinical drug-drug and drug-food interations. The present data confirms from a mechanistic point of
view these interactions.
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Intestinal absorption, Digoxin, Biopharmaceutic
Citação
CALDEIRA, T. G. et al. Determination of intestinal permeability using in situ perfusion model in rats : challenges and advantages to BCS classification applied to digoxin. International Journal of Pharmaceutics, v. 551, n. 1–2, p. 148-157, nov. 2018. Disponível em: <https://www.sciencedirect.com/science/article/pii/S0378517318306732?via%3Dihub>. Acesso em: 25 fev. 2019.