Development of an in vitro rat intestine segmental perfusion model to investigate permeability and predict oral fraction absorbed.
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.
Castella
Marc-Etienne
ME
LCT-Pharmacochemistry, School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, 30, Quai Ernest Ansermet, CH-1211, Geneva 4, Switzerland.
Reist
Marianne
M
Mayer
Joachim M
JM
Turban
Jean-Jacques
JJ
Testa
Bernard
B
Boursier-Neyret
Claire
C
Walther
Bernard
B
Delbos
Jean-Marie
JM
Carrupt
Pierre-Alain
PA
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
D004364:Pharmaceutical Preparations; D013739:Testosterone; D009288:Naproxen; C016904:norverapamil; D014700:Verapamil; D000983:Antipyrine