Colonic absorption, acids

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. 

Log D accounts for where the "dose" is, so to speak. The distribution depends on the pKa as well as the pH of the medium. The advantage of using log D is that it incorporates these factors, so, for simple processes such as absorption, distribution coefficients "ej lain" the whole process. An example from our earlier work ( ) is the colonic absorption of acids ranging from phenols to strong carboxylic acids. The absorption rate is given by an equation involving only log D terms. 

Sakai, K., et al. 1986. Contribution of calcium ion sequestration by polyoxyethylated nonionic surfactants to the enhanced colonic absorption of p-aminobenzoic acid. J Pharm Sci 75 387. 

Cundy, K. C., Annamalai, T., Bu, L., et al. XP13512 [( )-l-([(a-isobutanoyloxyethoxy) carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J. Pharmacol. Exp. Ther. 311 324-333, 2004. 

Longer chain fatty acids are also effective as intestinal permeation enhancers. Morishita et al. (1998), for instance, could significantly increase the in situ colonic absorption of insulin in rats utilizing emulsions (w/o/w) containing oleic, linoleic or linolenic acid. 

Rivera TM, Leone-Bay A, Paton DR, Leipold H, Baughman RA (1997) Oral delivery of heparin in combination with sodium N-[8-(2-hydroxybenzoyl) aminojcaprylate pharmacological considerations. Pharm Res 14 1830-1834 Sakai K, Kutsuna TM, Nishino T, Fujihara Y, Yata N (1986) Contribution of calcium ion sequestration by polyoxyethylated nonionic surfactants to the enhanced colonic absorption of p-aminobenzoic acid. J Pharm Sci 75 387-390 Sakai M, Imai T, Ohtake H, Azuma H, Otagiri M (1997) Effects of absorption enhancers on the transport of model compounds in Caco-2 cell monolayers assessment by confocal laser scanning microscopy. J Pharm Sci 86 779-785... 

For most formulations, colonic absorption represents the only real opportunity to increase the interval between doses. Transit through the lower part of the gut is quoted at about 24h, but in reality only the ascending colonic environment has sufficient fluid to facilitate dissolution. In the cecum, the fermentation of soluble fiber produces fatty acids and gas [33].The gas rises into the transverse colon and can form temporary pockets, restricting access of water to the formulation. Consequently, distal release of drug is associated with poor spreading, reduced surface area, and restricted absorption. In the colon, water availability is also low past the hepatic flexure, as the ascending colon is extremely efficient at water absorption [34],... 

In view of their solubilizing effects and also their potential to change membrane permeability, surfactants have been considered as absorption enhancers, again mostly in animals. Polyoxyethylene ethers have been shown to enhance gastric or rectal absorption of linco-mycin, penicillin, cephalosporins, and fosfomycin in rats and rabbits. In rats, colonic absorption of interferon-alpha is increased from 3 to 8% by polyoxyethylene esters of oleic acid and oleic acid glycerides. 

Colonic Absorption. In our earlier paper (1 ) we analyzed the absorption of acids and bases from the rat colon and compared these results with alternative analyses. We reported eq 4 for the bases (Table II), which compares favorably with eq 5 (5). (The absolute t-value is shown below each parameter.)... 

Colonic Absorption of Acids and Bases and Physiochemical Constants Used3... 

One important advantage of using log D s which hasn t been previously described is that acids, bases and neutral compounds can easily be combined into one analysis. The rate of colonic absorption at pH 6.8 of all the acids, bases and neutral compounds in Table II can be correlated by a simple equation using a single parameter, eq 6. These can not be correlated as well by any reasonable number of other terms. 

In an attempt to formulate a QSAR model for the colonic absorption of aromatic acids, phenols, and other acidic compounds, Lien [73] derived Eq. (38) ... 

Table 15. Colonic absorption of acidic compounds in a rat in situ model at pH = 6 8 [442, 469, 472]...

The colonic absorption of different acidic compounds is described by eq. 110 (chapter 4.5) [442]. 

Colonic reabsorption of secondary bile acids seems to be clearly established. The presence of deoxycholic acid as a normal biliary constituent indicates that it has been absorbed from the colon. Furthermore, the human bile contains a variety of other bacterial transformation products such as lithocholic acid and other cholanic acids, some of which may have been further metabolized by the liver (44-47). In contrast to the case in some other mammalian species, human liver is not able to convert deoxycholic acid back to cholic acid. Colonic perfusion with different labeled bile acids has clearly shown that colonic absorption takes place in man (48). Administration of labeled cholic acid into the lumen of the large bowel during operation for cholecystectomy is followed by the appearance of labeled cholic acid and deoxycholic acid in the T-tube bile, the recovery from the T-tube being about 60% of the dose (49). This clearly shows that cholic acid is converted to deoxycholic acid in the human colon and that both of them are absorbed from the large bowel. Colonic reabsorption has been calculated to amount to 200 mg/ day (49). The colonic absorption of secondary bile salts could be even higher if the physical state of some bile acids were not unfavorable for absorption. Lithocholic acid, for example, is a very nonpolar compound and precipitates in the colonic content in addition, it and other secondary bile acids as well are partially associated with fecal debris and bacteria (41). As a result of poor absorption, the amount of secondary bile acids, other than deoxycholic acid, is usually low in human bile. After a continuous biliary drainage, secondary bile acids disappear from the bile in a few days (49-51). 

Another chemical property of the MCT, water solubility, makes the MCT colon absorption possible, a very important process for the CD patients. Medium chain fatty acids are also energy sources for the patients which suffer from ulceration and inflammation in the intestine (Andoh et al., 2000). The nutrition plays an important role in the management of patients with IBD. It seems that a dose of MCT oil up to 50 g/day can be a good dose for patients with ileitis or an extensive resection of the small intestine, as osmotic diarrhea (Eiden, 2003). 

In culture, the human colon carcinoma cell hne Caco-2 spontaneously differentiates at confluency into polarized cells with enterocyte-like characteristics. The principle of this approach consists of following the passage of the compound of interest from the apical or lumen-like sides to the basolateral or lymph-hke sides of Caco-2 cells, thus following the absorption of the compound per se. One obhgate step for fat-soluble nutrients such as carotenoids to cross the intestinal barrier is their incorporation into CMs assembled in the enterocytes. Under normal cell culture conditions, Caco-2 cells are unable to form CMs. When supplemented with taurocholate and oleic acid, Caco-2 cells were reported to assemble and secrete CMs. ... 

After absorption in the small bowel, remaining undigested food passes from the ileum through the ileocecal valve to the colon. A major role of the colon is absorption of fluid. Some of the water and sodium absorption achieved by the colon is facilitated by short-chain fatty acids (SFCAs) formed from digestion of certain dietary fibers by colonic bacterial enzymes. 

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