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 (Fa) 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 value has been reported. However, in-situ techniques might provide a more accurate estimation of Fa. In this study, we evaluated a single-pass intestinal-perfusion (SPIP) method in the rat for its use in the prediction of absorption in man and compared it with a previous report using cell-based assays. Effective permeability coefficients (Peff) were determined in rats for 14 compounds, and ranged from 0.043x 10(-4) cm s(-1) to 1.67 x 10(-4) cm s(-1). These values strongly correlated (r2 = 0.88) with reported Peff values for man. In addition, the Spearman rank correlation coefficient calculated for in-situ-derived Peff and absorption in man was 0.92 while for the previously tested in-vitro Caco-2 and MDCK systems vs absorption in man, the correlation coefficients were 0.61 and 0.59, respectively. SPIP provided a better prediction of human absorption than the cell-based assays. This method, although time consuming, could be used as a secondary test for studying the mechanisms governing the absorption of new compounds, and for predicting more accurately the fraction absorbed in man.
Salphati
L
L
Affymax Research Institute, Santa Clara, CA 95051, USA. laurent_salphati@affymax.com
Childers
K
K
Pan
L
L
Tsutsui
K
K
Takahashi
L
L
D000818:Animals; D018938:Caco-2 Cells / Q000378:metabolism; D002460:Cell Line / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D006801:Humans; D007082:Ileum / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D010477:Perfusion / Q000379:methods*; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley