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.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of sodium taurocholate (TC) on the intestinal absorption of drugs was studied in vivo in a chronically isolated internal loop in the rat. The hydrophilic drugs paracetamol (PA) and theophylline (TP) and the lipophilic drugs griseofulvin (GF) and ketoconazole (KE) were used as model drugs. The drug concentrations were kept below the saturation concentration. Absorption kinetics of the drugs were evaluated on the basis of disappearance rates of the drug from luminal solutions in the intestinal loop. Concentrations of TC above the critical micelle concentration (CMC) did not affect the absorption rate of the hydrophilic drugs PA and TP; the barrier function of the intestinal wall for PA and TP was not altered in the presence of taurocholate. The addition of concentrations of TC above the CMC in the perfusion solution resulted in a reduction of the absorption rate of GF and KE. The reduction in the absorption kinetics of GF in the presence of TC correlated well with the reduction of the drug-free fraction in solution due to micellar solubilization. For KE this relation was less clear. It was not possible to determine, on the basis of the phase-separation model, to what extent the fraction of the drug incorporated in TC micelles contributes to the overall diffusion of GF and KE across the preepithelial diffusion barrier. It was concluded that TC exhibits only a minor, if not negligible, effect on the barrier function of the aqueous diffusion barrier adjacent to the intestinal wall.

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