Small intestine pumps

Figure 9.7 (a) The epithelial brush border cells of the small intestine concentrate glucose from the intestinal lumen in symport with Na+ this is driven by the (Na+-K+)-ATPase located on the capillary side of the cell. The glucose is then exported by a passive uniport system. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.) (b) Two Na+-binding sites in the LeuT Na+-dependent pump. (From Gouax and MacKinnon, 2005. Copyright (2005) American Association for the Advancement of Science.)... 

Permeation enhancement by excipients has generated some interest, but there is still much research that needs to be done to elucidate the mechanism of these excipients. PEG-400 (and many other excipients such as polyethylene glycol, poloxamers, polysorbates, and vitamin E) is known to inhibit p-glycoprotein, which may increase the bioavailability of the API, which was a substrate for this efflux pump. On the other hand, it has been demonstrated that PEG-400 can accelerate small intestinal transit, and thereby reduce the bioavailability of some drugs (e.g., ranitidine) (5). 

As indicated earlier in this chapter, these transporter proteins are found in a variety of cell types but especially in those organs exposed to chemicals from the environment (e.g., gastrointestinal tract), excretory organs (e.g., kidney), and sensitive organs (e.g., brain). The proteins are usually found on the luminal side of epithelial cells in organs of exposure, such as the small intestine, which allows the cells to pump out the potentially hazardous chemical. In sensitive organs such as the brain, the transporters are on that side of cells that will allow chemicals to be pumped back into the blood or interstitial fluid. In organs of excretion, such as the kidney, the transporters are located on the apical side of cells such as the proximal convoluted tubular cells. 

This transporter is particularly important in the small intestine, in the gut wall enterocytes, where its activity in humans is sevenfold higher than liver tissue. In the gut, pGp, acting in concert with cytochrome P-450 (CYP3A4) (see chap. 4), functions to keep chemicals, which may be potential toxicants, out of the body by pumping them back into the lumen of the gut. The CYP3A4 converts them into more polar compounds, which are less readily absorbed or further metabolized into water-soluble conjugates. 

As noted above, gastric acid serves as an important barrier to bacterial colonization of the stomach and small intestine. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors. An increase in nitrate-reductase positive strains could theoretically increase carcinogenic nitrites and N-nitrosamines. However, most studies do not demonstrate this. 

Therefore, increased bioavailability could be reached by using bioadhesive drug delivery systems, releasing the drug in the upper part of the small intestine where efflux pump activity is lower. 

Continuous drip or cyclic infusion 50 to 125 ml infused per hour at a slow rate over a 24-hour period using an infusion pump (Kangaroo set). Used for treating critically ill patients and patients who have a feeding tube in their small intestines. 

V. cholerae is a gram-negative baciUus sharing similar characteristics with the family Enterobacteriaceae. Most pathology of cholera results from an enterotoxin (cholera toxin) produced by the bacteria. Conditions that reduce gastric acidity, such as the use of antacids, histamine-receptor blockers, or proton pump inhibitors or infections with Helicobacter pylori, increase the risk for clinical disease. Cholera toxin stimulates adenylate cyclase, which increases intracellular cAMP and results in inhibition of sodium and chloride absorption by microvillli and promotes the secretion of chloride and water by crypt cells. The toxin likely acts along the entire intestinal tract, but most fluid loss occurs in the duodenum. The net effect of the cholera toxin is isotonic fluid secretion (primarily in the small intestine) that exceeds the absorptive capacity of the intestinal tract (primarily the colon). This results in the production of watery diarrhea with electrolyte concentrations similar to that of plasma. 

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