title: Development of an in vitro rat intestine segmental perfusion model to investigate permeability and predict oral fraction absorbed.
abstract: OBJECTIVE
  The aims of the study are to develop and evaluate an in vitro rat intestine segmental perfusion model for the prediction of the oral fraction absorbed of compounds and to assess the ability of the model to study intestinal metabolism.
  
  
  METHODS
  The system consisted of a perfusion cell with a rat intestinal segment and three perfusion circulations (donor, receiver, and rinsing circulation). Lucifer yellow (LY) was applied as internal standard together with test compounds in the donor circulation. To validate the model, the permeability of eight noncongeneric passively absorbed drugs was determined. Intestinal N-demethylation of verapamil into norverapamil was followed in the donor and receiver circulations by high-performance liquid chromatography analysis.
  
  
  RESULTS
  The in vitro model allowed ranking of the tested compounds according to their in vivo absorption potential. The Spearman's correlation coefficient between the oral fraction absorbed in humans and the ratio of permeation coefficient of test compound to the permeation coefficient of LY within the same experiment was 0.98 (P < 0.01). Moreover, intestinal N-demethylation of verapamil, its permeation, and the permeation of its metabolite norverapamil could be assessed in parallel.
  
  
  CONCLUSIONS
  Up to six permeation kinetics can be obtained per rat, and the method has shown to be a valuable tool to estimate human oral absorption.
authors.affiliation: LCT-Pharmacochemistry, School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, 30, Quai Ernest Ansermet, CH-1211, Geneva 4, Switzerland.
authors.forename: Marc-Etienne
authors.initials: ME
authors.lastname: Castella
authors.forename: Marianne
authors.initials: M
authors.lastname: Reist
authors.forename: Joachim M
authors.initials: JM
authors.lastname: Mayer
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Turban
authors.forename: Bernard
authors.initials: B
authors.lastname: Testa
authors.forename: Claire
authors.initials: C
authors.lastname: Boursier-Neyret
authors.forename: Bernard
authors.initials: B
authors.lastname: Walther
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Delbos
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000378:metabolism; D003640:Dealkylation; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009288:Naproxen / Q000378:metabolism; D010477:Perfusion / Q000295:instrumentation / Q000379:methods*; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism; D014700:Verapamil / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D013739:Testosterone; D009288:Naproxen; C016904:norverapamil; D014700:Verapamil; D000983:Antipyrine