RT Journal Article SR Electronic T1 INTESTINAL PERFUSION WITH MESENTERIC BLOOD SAMPLING IN WILD-TYPE AND KNOCKOUT MICE JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1334 OP 1337 DO 10.1124/dmd.109.026591 VO 37 IS 6 A1 Raf Mols A1 Joachim Brouwers A1 Alfred H. Schinkel A1 Pieter Annaert A1 Patrick Augustijns YR 2009 UL http://dmd.aspetjournals.org/content/37/6/1334.abstract AB In the present study, we successfully downscaled, for the first time, the in situ intestinal perfusion technique with mesenteric blood sampling from rat to mouse. To evaluate the feasibility of this approach, we assessed the apparent permeability (Papp) of mouse intestine for a set of marker compounds [atenolol, paracellular transport; metoprolol, transcellular transport; talinolol, P-glycoprotein (P-gp)-mediated efflux] in both wild-type and P-gp-deficient mice. In wild-type mice, the observed Papp values for atenolol (1.8 ± 0.3 × 10–6 cm/s) and metoprolol (50.2 ± 20.1 × 10–6 cm/s) were not significantly affected by inclusion of the P-gp inhibitor verapamil. In contrast, the Papp value for talinolol (0.9 ± 0.3 × 10–6 cm/s) increased 5-fold in the presence of verapamil. The similarity between these values and previously determined Papp values in rats indicates comparable passive barrier functions and P-gp-mediated efflux transport between mice and rats. In comparison with wild-type mice, the apparent permeability in P-gp-deficient mdr1a/1b(–/–) mice was significantly altered for talinolol (7-fold increase) but not for atenolol or metoprolol. Because of the availability of knockout mice, the intestinal perfusion technique with mesenteric blood sampling in mice may become an important tool to elucidate the role of intestinal metabolism and active transport in drug absorption during preclinical drug evaluation. The American Society for Pharmacology and Experimental Therapeutics