Isolated perfused intestine (assessment)

 

                        

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          Perfusion system                                                                        Application in Xenoblis

 

Passage of Antipyrine, Mannitol and a Pgp substrat through the isolated perfused rat intestine, mechanistic and predictive information on parent drug  and finished products

 

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   POSTER ABSTRACT  presented  at the EUFEPS & COST Conference on (BA) & (BE) 

                                                                                                 Athens. Greece October 1-2.2007

                     

ISOLATED AND PERFUSED SEGMENT INTESTINE -A USEFULL TOOL TO ASSESS 

THE APPARENT INTESTINAL PERMEABILITY (P app)

Béatrice Lopez1, Fabrice Guillet1,  Pierre Gires1, Marie-José Loyer-Lecestre2,   Brée Françoise1

1Xenoblis Parc d’Affaires de la Bretèche 35760 Saint Grégoire -  France;  2 Laboratoire d’Anatomie -Pathologie Centre Hospitalier 17000 La Rochelle - France

 The intestinal absorption is one important step in the development of a new chemical entity.In recent years, there has been a constant search for in vitro methods that are predictive of human drug absorption. Cellular models as Caco-2 or HT 29 have become widely used and accepted as useful models for the primary screening of NCE’s for intestinal absorption. However, they have numbers of limitations in discriminative analysis of mechanistic parameters and particularly for testing the efficiency of novel formulations for oral drug delivery. Xenoblis adapted a simple in vitro system for studying drug absorption. This model presents the advantage to be a dynamic model taking into account the intestinal motility as well as the presence of goblet cells secreting mucin, endocrine cells and M cells. Based on the well described incidence of the apical mucus layer for the drug absorption, this tissue-based approaches is an improved model compared to the monolayer cell one’s. In the same way the transepithelial electrical resistance is far higher in Caco2 cells than in intestine or in the perfused isolated intestinal segment, inducing an  underestimation of the paracellular way in the Caco2 cells model.

 Inspired by the everted sac method [1-2], this model of a segment of intestine perfused provides useful and complementary information to the sac system.  This model consist in an intestinal segment (duodenum, jejunum, or ileum) of around 10cm everted, perfused. The perfusion will avoid stagnant fluids inside the intestinal segment. It is mounted in a chamber containing the test active substance and formulations dissolved in TC199 medium to mimic the mucosal compartment at 37° C.  This perfused segment of rat intestine, not only acts as an absorptive barrier, but also as the first metabolic tissue encountered after oral drug absorption, thus preserves the biological and physiological intestine activity. The use of this model is a great asset in early development and estimation of human oral absorption of NCE’s.

 References

  1. Wilson T.H, Wiseman G. The use of everted small intestine for the study of the transference of substances from the mucosal to the serosal surface. J.Physiol 1954; 123:116-125.
  2. Lacombe O, Woodley J, Solleux C, Delbos J-M,  Boursier-Neyret C,  Houin G. Localisation of drug permeability along the rat small intestine, using markers of the paracellular, transcellular and some transporter routes. Eur. J. Pharm. Sci.. 2004; 23:385-391

 

                               

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