Azoreductase Sulphoxide reductase
Amdases & Esterases
Clostridia, lactobaccilli E. coli
Strep. Faecalis, eubacteria E. coli A. aerogenes
Streptococci, cloistridia Enerobacter sp.
Reduction of aromatic and heterocyclic nitrocompounds Reductive scission of azo-bonds Removal of oxygen from sulphoxides Hydrolysis of 3-glycosides Hydrolysis of fi-gluronides of phenols and alcohols Cleavage of O-sulphates Hydrolysis of amides or esters of carboxylic acids bacterium able to hydrolyze pectin resulted in a significant increase in indomethacin release, although the total amount released after 6 h was only about 20%.
Once a drug has been released into the colonic lumen it is possible for it to be metabolised by colonic bacteria, which may result in the release of toxic products or the metabolism of the active drug to an inactive metabolite. For example, the bioavailability of digoxin from a delayed release formulation is reduced when compared with its bioavailability from conventional formulations, due to its degradation by colonic bacteria to the inactive dihydro-digoxin109.
Drugs such as stilboestrol, morphine and indomethacin are excreted in the bile as inactive sulphate or glucuronic acid conjugates. These conjugates are metabolized by bacterial enzymes (Table 7.4) to release the active form of the drug, which can then be reabsorbed and prolong pharmacological action.
Effect of disease and co-medication on colonic drug absorption
Gastrointestinal diseases are known to have a significant effect on the absorption of some orally administered drugs. Enteric coated formulations designed for release in the colon have been shown to release their contents in the stomach of achlorhydric patients. Such patients may have bacterial overgrowth in the small intestine which could lead to the premature release of drugs such as sulphasalazine or sennosides, thus rendering the therapy ineffective, as the drug would be absorbed before reaching the colon.
Increased permeability of the mucosal lining, allowing entry of microbial or dietary antigens, has been proposed as a possible cause in the pathophysiology of chronic inflammatory bowel disease. Interestingly, in Crohn's disease of the colon, there is abnormal permeability in apparently uninvolved proximal small intestine as well as in the colon110. Patients with Crohn's disease are subject to gastrointestinal strictures where a controlled release matrix may lodge and cause epithelial damage due to the release of concentrated drug at one site over a prolonged period of time111.
Normal subjects have rapid diffuse spread of water soluble radioisotopes through the colon, with the majority of activity being lost to faeces after 24 h112. In patients with intractable constipation, some will show normal transit, but in those with colonic inertia the major site of isotope hold-up is the transverse colon and splenic flexure. Other constipated patients show delay of label at a later stage and accumulation of activity in the descending and rectosigmoid colon. Diarrhoea causes changes in the electrolyte and water content of the colonic lumen which therefore alters luminal pH, resulting in changes in the rate of absorption of drugs from the lumen. As a result the effectiveness of colonic delivery may be unpredictable in patients with constipation or diarrhoea. The increased rate of transit would also be responsible for the premature voiding of sustained release formulations, and would also be expected to alter the sieving function of the colon. Diarrhoeal diseases are known to cause decreased gut transit time, and hence incomplete metabolism, of pro-drugs such as sulphasalazine. To date, however, little detailed information exists in the literature concerning the effect of motility disorders on colonic delivery.
Was this article helpful?