Author(s): Salphati L, Childers K, Pan L, Tsutsui K, Takahashi L
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Abstract 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.
This article was published in J Pharm Pharmacol
and referenced in Journal of Bioequivalence & Bioavailability