Mucosal absorption

Kashi DS, and Lee VHL (1986) Enkephalin hydrolysis in homogenates of various absorptive mucosal of the albino rabbit Similarities in rates and involvement of aminopeptidases. Life Sci. 38 2019-2028. 

Increased permeability is just one prerequisite in the development of useful peptide prodrugs. Another condition is that efficient bioactivation must follow absorption. Mucosal cell enzymes able to hydrolyze peptides include exopeptidases such as aminopeptidases and carboxypeptidases, endopepti-dases, and dipeptidases such as cytosolic nonspecific dipeptidase (EC 3.4.13.18), Pro-X dipeptidase (prolinase, EC 3.4.13.4), and X-Pro dipeptidase (prolidase, EC 3.4.13.9). For example, L-a-methyldopa-Pro was shown to be a good substrate for both the peptide transporter and prolidase. This dual affinity is not shared by all dipeptide derivatives, and, indeed, dipeptides that lack an N-terminal a-amino group are substrates for the peptide transporter but not for prolidase [29] [33] [34],... 

Mechanisms Toxins Reduced absorption Mucosal invasion... 

The obligatory steps in TAG absorption are hydrolysis and solubilization of the hydrolytic products. Based on the physicochemical properties of lipids and luminal mucosal membranes, one can predict that (1) TAG and DAG may not permeate the absorptive mucosal membrane and that (2) only 2-MAG and primarily protonated FA can pass through the membrane by diffusion as free monomers in the aqueous phase near the luminal membrane. The efficiency of fat digestion is assured by an excess of pancreatic lipase. Lipase is secreted to the duodenum in about 1000-fold excess. Thus, under optimal conditions, 100 kg TAG could be hydrolyzed in 24 hours instead of the ingested 100 g fat in a normal diet. 

A micellar phase is formed in the intestinal lumen when the bile salt concentration exceeds the critical micellar concentration (approximately 3-4 mM). This concentration of bile salts is usually exceeded during normal digestion. Mixed micelles contain bile salts, fatty acids, monoglycerides, cholesterol, and other lipid-soluble molecules (including fat-soluble vitamins) and are considered to be the major route of delivery of the products of fat digestion to the absorptive mucosal cell. Other nonmicellar phases may coexist in the intestinal lumen with the micellar phase these include an oil phase and a viscous isotropic phase. 

Diarrhea is a common problem that is usually self-limiting and of short duration. Increased accumulations of small intestinal and colonic contents are known to be responsible for producing diarrhea. The former may be caused by increased intestinal secretion which may be enterotoxin-induced, eg, cholera and E. col] or hormone and dmg-induced, eg, caffeine, prostaglandins, and laxatives decreased intestinal absorption because of decreased mucosal surface area, mucosal disease, eg, tropical spme, or osmotic deficiency, eg, disaccharidase or lactase deficiency and rapid transit of contents. An increased accumulation of colonic content may be linked to increased colonic secretion owing to hydroxy fatty acid or bile acids, and exudation, eg, inflammatory bowel disease or amebiasis decreased colonic absorption caused by decreased surface area, mucosal disease, and osmotic factors and rapid transit, eg, irritable bowel syndrome. 

Vitamin B12 is special in as far as its absorption depends on the availability of several secretory proteins, the most important being the so-called intrinsic factor (IF). IF is produced by the parietal cells of the fundic mucosa in man and is secreted simultaneously with HC1. In the small intestine, vitamin B12 (extrinsic factor) binds to the alkali-stable gastric glycoprotein IF. The molecules form a complex that resists intestinal proteolysis. In the ileum, the IF-vitamin B 12-complex attaches to specific mucosal receptors of the microvilli as soon as the chymus reaches a neutral pH. Then either cobalamin alone or the complex as a whole enters the mucosal cell. 

In addition to its role in regulating calcium homeostasis, vitamin D is required for the intestinal absorption of calcium. Synthesis of the intracellular calciumbinding protein, calbindin, required for calcium absorption, is induced by vitamin D, which also affects the permeability of the mucosal cells to calcium, an effect that is rapid and independent of protein synthesis. 

Although iron deficiency is a common problem, about 10% of the population are genetically at risk of iron overload (hemochromatosis), and elemental iron can lead to nonen2ymic generation of free radicals. Absorption of iron is stricdy regulated. Inorganic iron is accumulated in intestinal mucosal cells bound to an intracellular protein, ferritin. Once the ferritin in the cell is saturated with iron, no more can enter. Iron can only leave the mucosal cell if there is transferrin in plasma to bind to. Once transferrin is saturated with iron, any that has accumulated in the mucosal cells will be lost when the cells are shed. As a result of this mucosal barrier, only about 10% of dietary iron is normally absorbed and only 1-5% from many plant foods. 

Proteinaceous phytochemicals can contain toxic epitopes that elicit defense responses for example gliaden and glutein peptides which cause celiac disease and other mucosal disorders (Tighe and Ciclitira, 1995 Van de Wal et al, 1999). The mucosal inflammation caused by feeding carnivorous Atlantic salmon diets with soybean meal decreases rates of nutrient absorption (Nordrum et al, 2000), whereas the detrimental influence of such diets is much less pronounced when fed to omnivorous fish, such as catfish and tilapia. 

O In CF, the cystic fibrosis transmembrane regulator (CFTR) chloride channel is dysfunctional and usually results in decreased chloride secretion and increased sodium absorption, leading to altered viscosity of fluid excreted by the exocrine glands and mucosal obstruction. 

The food, now in a liquid form known as chyme, passes through the pyloric sphincter into the duodenum, where stomach acid is neutralized. There is wide variation in lengths of the components of the small intestine (i.e., duodenum, jejunum, and ileum) between individuals (Table 98-1). Most absorption of digested carbohydrate and protein occurs within the jejunum. Most fat absorption occurs within the jejunum and ileum. In the small bowel, breakdown of macronutrients (i.e., carbohydrate, protein, and fat) occurs both within the lumen of the gut and at the intestinal mucosal membrane surface. The absorptive units on the intestinal mucosal membrane are infoldings known as... 

The third mucosal layer is that lining the entire length of the small intestine and which represents a continuous sheet of epithelial cells. These epithelial cells (or enterocytes) are columnar in shape, and the luminal cell membrane, upon which the microvilli reside, is called the apical cell membrane. Opposite this membrane is the basal (or basolateral) plasma membrane, which is separated from the lamina propria by a basement membrane. A sketch of this cell is shown in Fig. 5. The primary function of the villi is absorption. 

K0/w as measured in the rat intestine [15,16], As with other examples that are available, as K0/w increases, the rate of absorption increases. One very extensive study [17-19] has examined in depth the physicochemical factors governing nonelectrolyte permeability for several hundred compounds. This study employed an in vitro preparation of rabbit gallbladder, an organ whose mucosal surface is lined by epithelial cells. The... 

Not all transporters, however, show the same preferential directions. Lee and coworkers also have discovered a pump glycoprotein in the conjunctiva with preferential flux directed toward the mucosal side of the tissue. This transporter has been shown to restrict conjunctival absorption of therapeutic agents such as cyclosporin A, verapamil, and dexamethasone. In some circumstances, transient inhibition of such xe-nobiotic transporters might be an effective means of increasing the efficacy of particular classes of therapeutic agents. 

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. 

Membrane uptake of nonionized solute is favored over that of ionized solute by the membrane/water partition coefficient (Kp). If Kp = 1 for a nonionized solute, membrane permeability should mirror the solute ionization curve (i.e., membrane permeability should be half the maximum value when mucosal pH equals solute pKa). When the Kp is high, membrane uptake of nonionized solute shifts the ionization equilibrium in the mucosal microclimate to replace nonionized solute removed by the membrane. As a result, solute membrane permeability (absorption rate) versus pH curves are shifted toward the right for weak acids and toward the left for weak bases (Fig. 7). 

Figure 7 (Left panel) Relative absorption rate for a weak acid (pKa = 3) as a function of mucosal pH for increasing barrier (membrane) permeability (Pb) with fixed unstirred aqueous layer permeability (Pul). X = pHinflectionpoint in Eq. (4). (Right panel) Partition coefficient-dependent absorption rates for salicylic acid and the weak base ephedrine. (From Ref. 19.)...

The coupling of solute transport in the GI lumen with solute lumenal metabolism (homogeneous reaction) and membrane metabolism (heterogeneous reaction) has been discussed by Sinko et al. [54] and is more generally treated in Cussler s text [55], At the cellular level, solute metabolism can occur at the mucosal membrane, in the enterocyte cytosol, and in the endoplasmic reticulum (or microsomal compartment). For peptide drugs, the extent of hydrolysis by lumenal and membrane-bound peptidases reduces drug availability for intestinal absorption [56], Preferential hydrolysis (metabolic specificity) has been targeted for reconversion... 

Solute uptake can also be evaluated in isolated cell suspensions, cell mono-layers, and enterocyte membrane vesicles. In these preparations, uptake is normalized by enzyme activity and/or protein concentration. While the isolation of cells in suspension preparations is an experimentally easy procedure, disruption of cell monolayers causes dedifferentiation and mucosal-to-serosal polarity is lost. While cell monolayers from culture have become a popular drug absorption screening tool, differences in drug metabolism and carrier-mediated absorption [70], export, and paracellular transport may be cell-type- and condition-depen-dent. 

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