Mixed micelles lipid uptake

The absorption of drugs from the rectal [32] cavity has been studied in some detail. Muranishi et al. [34] have shown that a significant increase in the absorption and lymphatic uptake of soluble and colloidal macromolecules can be achieved by pretreating the rectal mucosal membrane with lipid-nonionic surfactant mixed micelles. They found no evidence of serious damage of the mucosal membrane. Davis [30] suggested that the vaginal cavity could be an effective delivery site for certain pharmaceuticals, such as calcitonin, used for the treatment of postmenopausal osteoporosis. 

Solubilization of lipid digestion products in intestinal mixed micelles enhances their dissolution and dramatically increases the GI lumen-enterocyte concentration gradient that drives absorption by means of passive diffusion. Micelles, however, are not absorbed intact [8, 9], and lipids are thought to be absorbed from a monomolecular intermicellar phase in equilibrium with the intestinal micellar phase [10], The dissociation of monomolecular lipid from the micellar phase appears to be stimulated by the presence of an acidic microclimate associated with the enterocyte surface [11,12], In addition to passive diffusion, growing evidence suggests that active uptake processes mediated by transport systems located in the enterocyte membrane are also involved in the absorption of (in particular) fatty acids into the enterocyte [4],... 

Fig. I. Overall scheme for cholesterol balance across the intestinal epithelial cell. After digestion, lipids in the intestinal lumen combine with bile acids to form mixed micelles (MM) that promote uptake into the intestinal epithelial cell. Within the intestinal cell, triglyceride and cholesterol, along with specific apoproteins, are synthesized into the chylomicron (CM) which, ultimately, delivers much of the triglyceride to peripheral organs and most of the cholesterol to the liver. Also shown in this diagram are the 3 major sources for epithelial cell cholesterol including (1) uptake from the lumen, (2) synthesis from acetyl-CoA and (3) uptake of low-density lipoproteins (LDL) by both receptor-dependent and receptor-indqjendent mechanisms.

A detailed investigation of the effect of micellar solubilization on the transport of lipids has been made by Westergaard and Dietschy [59]. They studied in vitro uptake of lipids into rabbit intestinal disks by varying the proportions of lipid and bile salts in mixed micelles in 3 different ways. Either lipid concentration was increased with bile salts kept at a constant level, lipid concentration was unchanged while bile salt concentration was varied, or both lipid and bile salt concentration was increased with the molar ratio kept constant. Theoretical calculations of how the mass of the lipid probe was distributed between the aqueous and the micellar compartment showed that there was a good correlation between calculated aqueous monomer concentration and experimentally obtained values for lipid uptake. The rate of uptake is thus proportional to the aqueous monomer concentration of a particular lipid. The conclusion drawn was that diffusion of the lipid molecules in monomeric form through the aqueous phase is an obligatory step before uptake into the plasma membrane, and that the role of bile salt is therefore to overcome the resistance of the unstirred water layer by micellar solubilization. 

Data on absorption of non-micellar lipids in the presence of bile salts is available from the study )y Knoebel [79]. The lymphatic transport of absorbed oleic acid and site of uptake from the intestinal lumen was measured in bile fistula rats. It was found that the concentration of bile salts in a continuous intraduodenal infusion did not affect the steady-state level of lipid appearing in the lymph until the bile salt concentration was as low as 1 mM, which represented a molar ratio of 20 1 of lipid to bile salt. In the case of infusates with relatively low concentrations of bile salts it was found that a larger part of the available surface area of the small intestine was utilized. The main conclusion is that lipids are equally well absorbed in vivo from non-micellar dispersions of lipids and bile salts as from solutions where the lipids are completely solubilized by bile salt mixed micelles. However, a detailed analysis of kinetics of uptake from non-micellar phases in vitro with isolated intestinal segments has not yet been done. 

Dietary retinyl esters must be hydrolyzed in the lumen of the small intestine before retinol is absorbed, while carotenoids must be absorbed into the intestinal mucosa before being cleaved intracel-lularly. Several enzymes with retinyl ester hydrolase (REH) activity are present in pancreatic juice or on the brush border of duodenal and jujenal enterocytes (Figure 3). Retinol and carotenoids must be solubilized in the lumen in mixed micelles composed of bile acids and products of lipid digestion prior to their uptake into enterocytes. These processes require the release of an adequate amount of bile... 

Thus, in contrast to previous in vivo models, this in vitro model provides the possibility of dissociating experimentally two important processes of the intestinal carotenoid absorption cellular uptake and secretion. Under conditions mimicking the postprandial state (TC OA supplementation), differentiated Caco-2 cells were able (1) to take up carotenoids at the apical side and to incorporate them into CM and (2) to secrete them at the basolateral side, associated with CM fractions. In this model, no attempt has yet been made to reproduce the in vivo physiochemical conditions occurring in the intestinal lumen, such as carotenoid release from the food matrix and solubilization into mixed lipid micelles. Carotenoids were delivered to Caco-2 cells in aqueous suspension with Tween 40 (During et al., 2002). Using this cell culture system in conjunction with an in vitro... 

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