Evaluation of a single-pass intestinal-perfusion method in rat for the prediction of absorption in man

Prediction of the fraction of dose absorbed from the intestine (F-a) in man is essential in the early drug discovery stage. In-vitro assays in Caco-2 and MDCK cells are routinely used for that purpose, and their predictive va lue has been reported. However, in-situ techniques might provide a more acc urate estimation of F-a. In this study, we evaluated a single-pass intestin al-perfusion (SPIP) method in the rat for its use in the prediction of abso rption in man and compared it with a previous report using cell-based assay s. Effective permeability coefficients (P-eff) were determined in rats for 14 compounds, and ranged from 0.043 x 10(-4) cm s(-1) to 1.67 x 10(-4) cm s (-1). These values strongly correlated (r(2) = 0.88) with reported P-eff va lues for man. In addition, the Spearman rank correlation coefficient calcul ated for in-situ-derived P-eff and absorption in man was 0.92 while for the previously tested in-vitro Caco-2 and MDCK systems vs absorption in man, t he correlation coefficients were 0.61 and 0.59, respectively. SPIP provided a better prediction of human absorption than the cell-based assays. This m ethod, although time consuming, could be used as a secondary test for study ing the mechanisms governing the absorption of new compounds, and for predi cting more accurately the fraction absorbed in man.