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±0.0756×10(-4) cm/s for ranitidine to 17.19±4.16×10(-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.
Department of Pharmacy and Pharmaceutical Technology, Biopharmaceutics and Pharmacokinetics Unit, School of Pharmacy, University of Barcelona, Joan XXIII s/n, E-08028 Barcelona, Spain. eescribano@ub.edu
Elvira
E
Escribano
Xavier García
XG
Sala
Jorge
J
Salamanca
Claudia Roig
CR
Navarro
Josep Queralt
JQ
Regué
D000658:Amoxicillin / Q000378:metabolism; D000818:Animals; D005665:Furosemide / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D023421:Models, Animal; D009288:Naproxen / Q000378:metabolism; D010477:Perfusion; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010894:Piroxicam / Q000378:metabolism; D011899:Ranitidine / Q000378:metabolism; D051381:Rats
D004364:Pharmaceutical Preparations; D010894:Piroxicam; D009288:Naproxen; D005665:Furosemide; D000658:Amoxicillin; D011899:Ranitidine