Proximal small intestine

NIELSEN K K, BUDDINGTON K K RAUN, K, HANSEN T K and BUDDINGTON R K. (2002) AbsOrption and systemic availability or two synthetic growth hormone secretogogues and transport of glucose by the proximal small intestine of anestrus dogs after administering estradiol. J Comp Physiol. In press. 

Although there is no data relating to free-radical activity in humans, several animal models have been developed (Parks etal., 1983). Pitt etal. (1991) showed that more severe injury occurred in the proximal small intestine, where levels of XO were highest. SOD has been reported to be protective in a rat model (Dalsing et al., 1983) and more recently a tungsten-supplemented diet was also found to be of benefit (Pitt et al., 1991). However, whether such treatment could modify the human disease, which usually develops within 10 days of birth, remains to be seen. 

The gastrointestinal microflora provide another potential site for drug metabolism within the GIT, and it has received some attention. In normal subjects the stomach and proximal small intestine contain small numbers of microorganisms. Concentrations of these organisms increase toward the distal end of the intestine. A wide variety of aerobic and anaerobic organisms are present in the gut. The microflora, derived primarily... 

Husebye E, Hauer-Jensen M, Kjorstad K, Skar V Severe late radiation enteropathy is characterised by impaired motility of proximal small intestine. Dig Dis Sci 1994 39 2341-2349. 

The solubility should be measured at all of these pH values with a suitable, validated method such as shake-flask or pSol (2) at 37°C to determine whether the (envisaged) dose of the drug can be completely dissolved at all points of interest in the GI tract (see Chapter 11 for more discussion of solubility determination). Typically, this would be the upper GI pH (stomach and proximal small intestine) for immediate release (IR) products, the pH in the small intestine for enteric-coated products and, additionally for MR dosage forms intended to release over a period of six hours or more, the pH in the proximal colon. 

The fact that the luminal pH of the healthy distal colon is slightly higher than that of the proximal small intestine has led to the development of oral dosage forms that are intended to release the drug at the colonic pH (pH-controlled drug release). 

The pharmacokinetic profile is different with different compounds. Diazepam after oral administration is completely and rapidly absorbed from the proximal small intestine. Oxazepam is least rapidly absorbed while lorazepam is an intermediately absorbed between these two. They are metabolised in liver by dealkylation and hydroxylation and excreted in urine as glu-curonide conjugates. They cross the placental barrier and are secreted in milk. 

Drugs that contain 5-aminosalicylic acid (5-ASA) have been used successfully for decades in the treatment of inflammatory bowel diseases (Figure 62-8). 5-ASA differs from salicylic acid only by the addition of an amino group at the 5 (meta) position. Aminosalicylates are believed to work topically (not systemically) in areas of diseased gastrointestinal mucosa. Up to 80% of unformulated, aqueous 5-ASA is absorbed from the small intestine and does not reach the distal small bowel or colon in appreciable quantities. To overcome the rapid absorption of 5-ASA from the proximal small intestine, a number of formulations have been designed to deliver 5-ASA to various distal segments of the small bowel or the colon. These include sulfasalazine, olsalazine, balsalazide, and various forms of mesalamine. 

In vivo studies using mouse models have proved that curcumin modifies apoptosis resistance, leading to the inhibition of tumor formation and the prevention of adenoma development in the intestinal tract. The chemopreven-tive effect of curcumin for intestinal tumors in Min/+ mice was investigated. A dietary level of 0.15% curcumin decreased tumor formation in Min—/— mice by 63%. Examination of intestinal tissue from the treated animals showed the tumor prevention by curcumin was associated with increased enterocyte apoptosis and proliferation. Curcumin also decreased expression of the oncoprotein (S-catenin in the erythrocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. Curcumin enhanced PhlP-induced apoptosis and inhibited PhIP-induced tumorigenesis in the proximal small intestine of Ape (min) mice. Experiments performed on intestinal tumors in C57BL/6J-Min/+ (Min/+) mice demonstrated that curcumin has a regulatory role in lymphocyte-mediated immune function [Churchill et al., 2000]. Furthermore, levels of COX-2 protein expression have been found to reflect the retardation of adenoma development in mouse intestines after treatment with curcumin [Tunstall et al., 2006]. 

Phosphonoformic acid (Foscarnet), an antiviral drug, which consists of carboxylic acid and phosphate linked together, was shown to be absorbed in the small intestine by the phosphate carrier-mediated mechanism [154], The transport of folic acid was investigated in biopsy specimens of intestinal mucosa from healthy volunteers. A pH-dependent, active transport of folic acid was found in the proximal small intestine, whereas in the mucosa of the colon, folic acid uptake was driven by a facilitated diffusion, mediated by a low-affinity carrier [155]. The existence of folate receptors in the human colonic mucosa is logical due to the large amounts of folic acid produced by the colonic flora [145],... 

Fu, J., Kim, J., Oveisi, F., Astarita, G., and Piomelli, D. (2008). Targeted enhancement of oleoylethanolamide production in proximal small intestine induces across-meal satiety in rats. Am.J. Physiol Regul Integr. Comp. Physiol 295, R45—R50. 

Phylloquinone is absorbed in the proximal small intestine, by an energy-dependent mechanism, and is incorporated into chylomicrons. Estrogens increase phylloquinone absorption in both male and female animals, and male animals are more susceptible to dietary vitamin K deprivation than females (loUy et al., 1977). Even after an overnight fast, about half the plasma vitamin K is present in chylomicron remnants, and only a quarter in low-density lipoprotein. The plasma concentration of phylloquinone is associated with genetic variants of apoprotein E, which determines the binding of chylomicron remnants to the liver lipoprotein receptor (Kohlmeier et al., 1996). 

Paine ME, Ludington SS, Chen ML, Stewart PW, Huang SM. Does sex influence proximal small intestinal CYP3A or P-gp expression Clin Pharmacol Ther 2005 77 P2. 

Figurc 2-39 describes an experiment involving caiuiulation of the bile ducts of guinea pigs to penrit collection of bile salts flowing from the liver The data demonstrate two points. First bile salt introduced into the gut can be transported to the liver and then secreted through the bile duct. Second, the bile salt is absorbed not by the proximal small intestine, but by the distal small intestine.

First-pass intestinal metabolism. This includes brush border metabolism and intracellular metabolism. The former occurs at the surface of the enterocytes by the enzymes present within the brush border membrane. Furthermore, the brush border activity is generally greater in the proximal small intestine (duodenum jejunum > ileum colon) and involves enzymes such as alkaline phosphatase, sucrase, isomal-tase, and a considerable number of peptidases. ... 

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