Institution: | aLaboratoire de Cinétique des Xénobiotiques, UMR 181 Physiopathologie et Toxicologie Expérimentale (UPTE INRA-ENVT), Faculté des Sciences Pharmaceutiques, 35 chemin des Maraîchers, 31062 Toulouse Cedex, France bTechnologie Servier, Pharmacokinetic Department, 25–27 rue Eugene Vignat, 45000 Orléans, France cLaboratoire de Toxicologie et Pharmacocinétique Clinique, C.H.U. Rangueil, 31403 Toulouse Cedex 4, France |
Abstract: | The small intestine is the major site of drug absorption. Some reports in the literature have evoked the concept of “absorption windows” in the small intestine: are there specific regions where drug absorption is significantly higher than others? To investigate this question, we used an everted gut sac method to study the permeability of drugs and markers every 3–4 cm down the entire small intestine in rat. These markers were chosen to be representative of the mechanisms by which drugs cross the small intestinal mucosa: paracellular and transcellular passive diffusion, via influx transporters, and a drug (digoxin) that is effluxed from cells by P-glycoprotein (P-gp). The passive diffusion and influx transporter markers gave similar profiles with a plateau of permeability along the jejunum, and with the exception of L-Dopa, lower permeability in the ileum. Digoxin showed a linear decrease in the profile from the proximal jejunum to the ileum. Permeability in the duodenum was two to three times lower than the jejunum for all compounds. There were no narrow specific regions of high permeability and so the concept of discrete “absorption windows” along the small intestine as suggested from some pharmacokinetic studies may be related to other effects such as pH and/or solubility. |