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Intestinal Absorption of Drugs. The Influence of Mixed Micelles on on the Disappearance Kinetics of Drugs from the Small Intestine of the Rat

Abstract— The solubilization of the hydrophilic drugs paracetamol and theophylline, and the lipophilic drugs dantrolene, griseofulvin and ketoconazole has been determined in mixed micellar aqueous dispersions composed of 10 mM taurocholate + 5 mM oleic acid. The solubilization of dantrolene and paracetamol has also been determined in aqueous (mixed) micellar dispersions of 1 g L−1 lysophosphatidyl‐choline (LPC), or taurocholate/LPC. The influence of these (mixed) micelles on the absorption of the model drugs from solution was studied in the rat chronically isolated internal loop. Absorption kinetics of the drugs were evaluated on the basis of the disappearance rate of the drug dissolved in the perfusion medium in this loop. Absorption experiments with taurocholate/oleic acid in the perfusate resulted in a reduction of the disappearance rate for the lipophilic drugs and the hydrophilic drug theophylline. This could partly be ascribed to the decreased fraction of drug free in solution as a result of its micellar solubilization for dantrolene, griseofulvin and ketoconazole, but the decrease in the disappearance rate of theophylline was unexpected. Taurocholate/oleic acid, LPC and taurocholate/LPC micelles had no effect on the disappearance of paracetamol. The disappearance rate of dantrolene in the presence of LPC alone was not altered, in spite of the decreased fraction of the drug free in solution owing to its micellar solubilization. In contrast, taurocholate/LPC micelles caused a reduction in the rate of disappearance of dantrolene, as expected according to the phase‐separation model. In‐vitro, taurocholate and taurocholate/LPC reduced the molecular cohesion of porcine intestinal mucus, whereas LPC alone did not exhibit an effect on the gel structure of mucus. It is concluded that the transfer of solutes across the pre‐epithelial aqueous diffusion layer (including the mucus) and the epithelium is unaltered by (mixed) micelles at concentrations in the physiological range.