Intestinal mucosa metabolic activity

Pharmacokinetics Readily absorbed from the G1 tract. Widely distributed. Primarily concentrated in the liver. Metabolized in the liver and intestinal mucosa to active metabolite. Primarily excreted in urine. Half-life 15 min metabolite, 30-35 min. 

Mechanistic studies have shown that TBT and certain other forms of trialkyltin have two distinct modes of toxic action in vertebrates. On the one hand they act as inhibitors of oxidative phosphorylation in mitochondria (Aldridge and Street 1964). Inhibition is associated with repression of ATP synthesis, disturbance of ion transport across the mitochondrial membrane, and swelling of the membrane. Oxidative phosphorylation is a vital process in animals and plants, and so trialkyltin compounds act as wide-ranging biocides. Another mode of action involves the inhibition of forms of cytochrome P450, which was referred to earlier in connection with metabolism. This has been demonstrated in mammals, aquatic invertebrates and fish (Morcillo et al. 2004, Oberdorster 2002). TBTO has been shown to inhibit P450 activity in cells from various tissues of mammals, including liver, kidney, and small intestine mucosa, both in vivo and in vitro (Rosenberg and Drummond 1983, Environmental Health Criteria 116). 

Estradiol is the predominant and most active form of endogenous estrogens. Given orally, it is metabolized by intestinal mucosa and liver (10% reaches the circulation as free estradiol), and resultant estrone concentrations are three to six times those of estradiol. 

Estrogens are administered orally, parenterally by injection or as subcutaneous implants, transdermally and topically. After oral administration a considerable first pass effect, both in the intestinal mucosa and in the liver, takes place with large interindividual variability. Estrogens are hydroxylated and conjugated in the liver and excreted mainly in the bile. The conjugates can be hydrolyzed in the intestine to active compounds that are reabsorbed again. Their hepatic oxidative metabolism is increased by enzyme inducers and the enterohepatic circulation may be decreased by some antibiotics which disturb the intestinal bacterial flora. 

Many CYP3A substrates are also subject to efflux transport by P-gp at the intestinal mucosa (88-90). As discussed above, P-gp is inducible via activation of nuclear orphan receptors by the same inducers of CYP enzymes (91). Accordingly, for those drugs which are substrates of both CYP and P-gp, reduction in intestinal availability following treatment with known microsomal enzyme inducers could reflect the joint effects of increased mucosal metabolism and apical efflux. 

The in vivo metabolism of capecitabine (1) to the active tumor cytotoxic substance 5-fluorouracil (5) is now fairly well understood. When capecitabine is administered orally it is delivered to the small intestine, where it is not a substrate for thymidine phosphorylase in intestinal tissue, and so passes through the intestinal mucosa as an intact molecule and into the bloodstream. When 1 reaches the liver, the carbamate moiety is hydrolyzed through the action of carboxylesterase enzymes, liberating 5 -deoxy-5-fluorocytidine (5 -DFCR, 10). DFUR is partially stable in systemic circulation, but eventually diffuses into tumor cell tissue where it is transformed into 5 -deoxy-5-fluorouridine (5 -DFUR, 9) by cytidine deaminase, an enzyme present in high concentrations in various types of human cancers compared to adjacent healthy cells (although it is present in significantly lower levels in the liver). Within the tumor, 5-... 

Metabolic Transit of Free Radioactive e-(y-Glutamyl) lysine. The first metabolic study of this isopeptide was made by Waibel and Carpenter (81) who showed that this molecule was present in the blood plasma of chicks and rats receiving it in their diet. Using c-(y-glutamyl)-[4,5-3H] -lysine, Raczynski et al. (82) confirmed that the isopeptide passed unchanged across the intestinal wall into the serosal fluid in everted sacs and found that the kidneys were very active in hydrolyzing this isopeptide. These authors also found small hydrolytic activities in the intestinal mucosa and the liver. 

Both drugs and compounds naturally present in foods may compete with vitamins for absorption. Chlorpromazine, tricyclic antidepressants, and some antimalarial dmgs inhibit the intestinal transport and metabolism of riboflavin (Section 7.4.4) carotenoids lacking vitamin A activity compete with /S-carotene for intestinal absorption and metabolism (Section 2.2.2.2) and alcohol inhibits the active transport of thiamin across the intestinal mucosa (Section 6.2). 

Intestinal Blood Flow. The mechanistic relationship among intestinal blood flow and absorption, secretion, and metabolic activity of the intestinal mucosa is unclear. However, there is evidence that impaired intestinal blood flow rate correlates with a decrease in drug absorption rate. It has been postulated that reduced blood flow slows down the absorption rate... 

Whereas many cephalosporins such as cefaclor, cefadroxil, cefonicid, ceforanide, ceftazidime, cefti-zoxime, cefuroxime, cephalexin, and cephradine are not metabolized, cefamandole naftate is rapidly hydrolyzed in plasma to cefamandole, which has greater antibacterial activity than the parent compound. Ceftriaxone is metabolized to a small extent to micro-biologically inactive metabolites in the intestines after biliary excretion. Cefuroxime axetil is rapidly hydrolyzed to cefuroxime, the microbiologically active form of the drug, by nonspecific esterases in the intestinal mucosa and blood following oral administration. The axetil moiety is further metabolized to acetaldehyde and acetic acid [93]. 

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