Single-pass intestinal perfusion to establish the intestinal permeability of model drugs in mouse

The aim of the present work was to study the intestinal permeabilities (P-eff) of five model drugs: furosemide, piroxicam, naproxen, ranitidine and amoxicillin in the in situ intestinal perfusion technique in mice and compare them with corresponding rat and human in vivo P-eff values. The main experimental conditions were: mice CD1 30-35 g, test drug concentrations in perfusion experiments (the highest dose strength dissolved in 250 mL of PBS pH 6.2) and flow rate of 0.2 mL/min. The test compounds were assayed following a validated HPLC method. The effective permeability coefficients at steady-state were calculated after correcting the outlet concentration following the gravimetric correction method proposed by Sutton et al. (2001). The permeability coefficient values ranged from 0.1751 +/- 0.0756 x 10(-4) cm/s for ranitidine to 17.19 +/- 4.16 x 10(-4) cm/s for naproxen. The mouse method correctly assigned the BCS permeability classification of a given drug and a correlation between mouse permeability data and the fraction of an oral dose absorbed in humans was achieved (FA = 1 -exp(-34,745.P-eff(mouse)); R = 0.9631). Based on the results obtained, we conclude that mouse can be considered a valuable tool in the evaluation of intestinal permeability in order to predict the extent of human gastrointestinal absorption following oral administration of a drug. (c) 2012 Elsevier B. V. All rights reserved.