Differentiated intestinal epithelial cell lines as in vitro models for predicting the intestinal absorption of drugs.
The oral absorption of a compound is a critical factor for the future of the compound as a drug. This absorption is mainly controlled by the passage across the intestinal epithelium. Thus, the prediction of the intestinal absorption by means of an in vitro model may represent a powerful tool for the early selection of molecules during the process of drug development. In the present study, the differentiated human intestinal epithelial cell line HT29-18-C1, was grown on permeable filters in dual chambers. These cells formed tight monolayers that were used to measure in vitro the transepithelial permeability coefficient (Pc) of various molecules. The results were compared with in vivo data of oral absorption. A threshold value of in vitro permeability of 2 x 10(-6) cm/s was found. Molecules having a permeability coefficient higher than this value were absorbed orally more than 80%, while drugs with Pc values lower than 2 x 10(-6) cm/s were poorly absorbed. By mathematical simulation, it was found that this Pc value, when extrapolated to the surface area and volume of the small intestine, corresponds to an absorption of 80% for a compound with a transit time through the small intestine of 5 h. This demonstrates the predictive utility of the threshold value of the permeability coefficient derived from the in vitro model of intestinal epithelium.
Wils
P
P
UMR 133 CNRS/RPR, Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Warnery
A
A
Phung-Ba
V
V
Scherman
D
D
D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology; D004848:Epithelium / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D009093:Mucus / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D010599:Pharmacokinetics; D011237:Predictive Value of Tests
D004364:Pharmaceutical Preparations