Abstract
The mechanism of the nonlinear concentration dependence of the intestinal absorption of fluorescein isothiocyanate dextran 4,000 (FD-4) was studied using in situ rat intestinal loops and the in vitro Ussing-type chamber method. The intestinal absorption rate constant of FD-4, as evaluated by the intestinal loop method, increased significantly in a nonlinear fashion as the FD-4 concentration increased up to 0.2 mM and tended to decrease at concentrations higher than 0.2 mM. The mucosal-to-serosal permeation of FD-4 across rat ileal sheets, as evaluated by the in vitro Ussing-type chamber method, also increased in a nonlinear fashion in the low concentration range (0.01 - 0.02 mM), before decreasing as the concentration increased further, whereas serosal-to-mucosal permeation decreased in a concentration-dependent manner. In addition, mucosal-to-serosal flux and serosal-to-mucosal flux were increased and reduced in the presence of the metabolic inhibitor 2, 4-dinitrophenol, respectively. These results suggest that FD-4 is predominantly secreted into the intestinal lumen by an efflux transport system.
Highlights
Under normal conditions, the intestinal epithelium acts as a selective barrier that defines and maintains distinctive luminal and subepithelial compartments
The relationship between the first-order absorption rate constant and the FD-4 concentration was evaluated by the loop method
The results obtained in the present study represent the first evidence that a complex pattern of nonlinear FD-4 bioavailability is generated by the interaction of intestinal absorptive and secretory transport systems when FD-4 is present at a concentration beyond that which induces linear absorbability in the intestinal luminal fluid
Summary
The intestinal epithelium acts as a selective barrier that defines and maintains distinctive luminal and subepithelial compartments. The barrier function of the intestine permits the systemic absorption of nutrients while it prevents systemic contamination by luminal microbes or microbial products [1]. In both clinical and experimental studies, the functional integrity of the intestinal epithelial barrier has often been assessed by measuring the mucosal permeability of certain hydrophilic compounds, such as 51Cr-EDTA [2], lactulose [3], cellobiose [4], polyethylene glycols [5], fluorescent dyes [6], and fluorescein isothiocyanate (FITC)-labeled dextrans [7]. In some in vivo experimental studies, permeability was measured in the lumen-to-plasma direction [5]; whereas in others, permeability was measured in the plasma-to-lumen direction [7], and both types of studies were performed under the assumption that directional permeation involves passive diffusion and is not polarized
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