Gut wall

A number of muscle relaxants are useful anthelmintic agents. They cause the parasites to relax their attachment to t he gut wall so that they can be eliminated. One such agent s carbantel 9), Its synthesis follows the classic pattern of r eaction of 4-chlorophenyl isocyanate with ji -amylamidine. ... 

Bacillus thuringiensis produces a variety of organic compounds which are toxic to the larvae of certain susceptible insect hosts. Among the toxic entities are proteinaceous crystals, probably three soluble toxins, and certain enzymes. The protein material is the major toxin active in killing lepidopterous larvae. The protein is formed by the cells apparently in close synchrony with sporulation, and its nature is a constant function of bacterial strain. The mode of action of the protein is under study. The sequence of events in the pathology observed is probably solubilization of the crystal (enzymatic or physical)—>liberation of toxic unit—>alteration of permeability of larval gut wall— change in hemolymph pH—>invasion of hemolymph by spores or vegetative cells of the bacterium. 

The second type of material includes spores, which may or may not produce disease symptoms but which can germinate in the insect gut and give rise to vegetative bacterial cells which in turn may produce, and exoenzymes such as phospholipases (lecithinases) or hyaluronidase. The phospholipases may produce direct toxic symptoms owing to their action on nervous or other phospholipid-containing tissue. Hyaluronidase breaks down hyaluronic acid and produces effects on animal tissue which are morphologically similar to the breakdown of insect gut wall in the presence of microbial insecticide preparations. 

Catechol O-methyltransferase (COMT) is a widespread enzyme that catalyzes the transfer of the methyl group of S-adenosyl-l-methionine (AdoMet) to one of the phenolic group of the catechol substrate (Fig. 1). High COMT activity is found in the liver, kidney and gut wall... 

First-pass metabolism is the elimination of an orally administed drug by the liver or sometimes the gut wall, before it reaches the systemic circulation. First-pass metabolism results in a decreased systemic bioavailability. 

In the gut, many pathogens adhere to the gut wall and produce their toxic effect via toxins which pervade the surrounding gut wall or enter the systemic circulation. Vibrio cholerae and some enteropathic E. coli strains localize on the gut wall and produce toxins which increase vascular permeability. The end result is a hypersecretion of isotonic fluids into the gut lumen, acute diarrhoea and consequent dehydration which may be fatal in juveniles and the elderly. In all these instances, binding to epithelial cells is not essential but increases permeation ofthe toxin and prolongs the presence of the pathogen. 

Drugs taken orally are slow to act. Most are absorbed in the small intestine where the villi, which penetrate into the lumen, present a large surface area. Unfortunately in order to pass through the gut wall into the bloodstream the drug has to become dissolved in its cell s membranes and to achieve this it needs to be lipid-soluble. 

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous "cheese reaction". The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Fike amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because... 

Poorly absorbed compounds have been identified as those with a PSA>140Af Considering more compounds, considerable more scatter was found around the sigmoidal curve observed for a smaller set of compounds [74]. This is partly due to the fact that many compounds do not show simple passive diffusion only, but are affected by active carriers, efflux mechanisms involving P-glycoprotein (P-gp) and other transporter proteins, and gut wall metabohsm. These factors also con-... 

Humans Hydrogen peroxide has been used as an enema or as a cleaning agent for endoscopes and may cause mucosal damage when applied to the surface of the gut wall. Hydrogen peroxide enteritis can mimic an acute ulcerative, ischaemic or pseudomembranous colitis, and ranges from a reversible, clinically inapparent process to an acute, toxic fulminant colitis associated with perforation and death (Bilotta and Waye, 1989). It is conceivable that anecdotal reports of exacerbation of IBD by iron supplementation (Kawai et al. 1992) are mediated by hydroxyl radical production by the Fenton reaction. 

The promise of the isolation and production of therapeutic polypeptides and proteins demands that for treatment of a chronic disease state an oral delivery system be developed which will protect these valuable agents from the hostile gastric environment. Subsequently, the drugs will have to be completely released in the intestine, preferably in a state that will enhance their rapid dissolution and transport across the gut wall minimizing interaction with intestinal proteases. 

Drug molecules may be chemically or metabolically altered at various sites along the GIT including within gut fluids, within the gut wall, and by microorganisms present in the low end of the tract. These sites are noted in Fig. 18. Several examples of enzymatic... 

For this calculation, it is unnecessary to assume that Vd and/or kei are the same for the two studies. It is only necessary that fe be the same in both studies. This is usually a valid assumption unless the drug undergoes a significant amount of first-pass metabolism in the gut wall or liver following oral administration or a significant amount of decomposition at an intra muscular (IM) injection site. When this occurs, the availability of the extravascular dosage form may appear to be low, but the fault will not lie with the formulation. The bioavailability will be a true reflection of the therapeutic efficacy of the drug product, and reformulation may not increase bioavailability. 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

A direct in vivo assessment of the quantitative importance of gut wall metabolism and transport of drugs and metabolites in humans is difficult and consequently has been attempted only rarely [3, 6, 11, 12, 15, 16, 23, 25-32, 34, 35, 81]. The most direct in vivo approach to investigating these processes in drugs with variable and incomplete bioavailability was intestinal perfusion by single-pass per-... 

Fraction escaping gut wall first-pass extraction... 

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