Oral mucosa metabolic activity

The human gastrointestinal mucosa synthesizes a number of prostaglandins (see Chapter 18) the primary ones are prostaglandins E and F. Misoprostol, a methyl analog of PGE1, has been approved for gastrointestinal conditions. After oral administration, it is rapidly absorbed and metabolized to a metabolically active free acid. The serum half-life is less than 30 minutes hence, it must be administered 3-4 times daily. It is excreted in the urine however, dose reduction is not needed in patients with renal insufficiency. 

In general, it can be said that enzyme levels are generally lower in the mouth than, for example, levels present in the gastrointestinal tract. Again, this lower metabolic activity makes the oral mucosa an attractive route for the delivery of enzymatically labile biopharmaceuticals. 

While the metabolic activity of the oral cavity towards peptides and proteins is less than that of the GI tract, it should be recognized that the oral mucosa and secretions do have the ability to degrade drugs and that measures might be necessary to overcome this. 

Compared with some of the other mycotoxins such as aflatoxin, the trichothecenes do not appear to require metabolic activation to exert their biological activity.50 After direct dermal application or oral ingestion, the trichothecene mycotoxins can cause rapid irritation to the skin or intestinal mucosa. In cell-free systems or single cells in culture, these mycotoxins cause a rapid inhibition of protein synthesis and polyribosomal disaggregation.35 47 50 Thus, we can postulate that the trichothecene mycotoxins have molecular capability of direct reaction with cellular components. Despite this direct effect, it is possible to measure the toxicokinetics and the metabolism of the trichothecene mycotoxins. 

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. 

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-... 

Disposition in the Body. Rapidly absorbed from the small bowel after oral administration and widely distributed in the tissues less than 1% of a dose reaches the brain bioavailability about 33%. Extensively metabolised mainly by decarboxylation to dopamine, which is further metabolised, and also by methylation to 3-0-methyldopa which accumulates in the central nervous system most of a dose is decarboxylated by the gastric mucosa before entering the systemic circulation the decarboxylase activity is inhibited by carbidopa and benserazide. Dopamine is further metabolised to noradrenaline, 3-methoxytyramine, and to the two major excretory metabolites, 3,4-dihydroxyphenyl-acetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA). During prolonged therapy, the rate of levodopa metabolism appears to increase, possibly due to enzyme induction. About 70 to 80% of a dose is excreted in the urine in 24 hours. Of the material excreted in the urine, about 50% is DOPAC and HVA, 10% is dopamine, up to 30% is... 

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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