Physiological Pharmaceutics

Colon and rectal drug delivery 165Table 7.4 Bacterial metabolism of some drugsbacterium able to hydrolyze pectin resulted in a significant increase in indomethacin release,although the total amount released after 6 h was only about 20%.Bacterial degradation of drugOnce a drug has been released into the colonic lumen it is possible for it to be metabolisedby colonic bacteria, which may result in the release of toxic products or the metabolism ofthe active drug to an inactive metabolite. For example, the bioavailability of digoxin froma delayed release formulation is reduced when compared with its bioavailability fromconventional formulations, due to its degradation by colonic bacteria to the inactivedihydro-digoxin 109 .Drugs such as stilboestrol, morphine and indomethacin are excreted in the bile asinactive sulphate or glucuronic acid conjugates. These conjugates are metabolized bybacterial enzymes (Table 7.4) to release the active form of the drug, which can then bereabsorbed and prolong pharmacological action.Effect of disease and co-medication on colonic drug absorptionGastrointestinal diseases are known to have a significant effect on the absorption of someorally administered drugs. Enteric coated formulations designed for release in the colonhave been shown to release their contents in the stomach of achlorhydric patients. Suchpatients may have bacterial overgrowth in the small intestine which could lead to thepremature release of drugs such as sulphasalazine or sennosides, thus rendering the therapyineffective, as the drug would be absorbed before reaching the colon.Increased permeability of the mucosal lining, allowing entry of microbial or dietaryantigens, has been proposed as a possible cause in the pathophysiology of chronicinflammatory bowel disease. Interestingly, in Crohn’s disease of the colon, there is abnormalpermeability in apparently uninvolved proximal small intestine as well as in the colon 110 .Patients with Crohn’s disease are subject to gastrointestinal strictures where a controlledrelease matrix may lodge and cause epithelial damage due to the release of concentrateddrug at one site over a prolonged period of time 111 .Normal subjects have rapid diffuse spread of water soluble radioisotopes through thecolon, with the majority of activity being lost to faeces after 24 h 112 . In patients withintractable constipation, some will show normal transit, but in those with colonic inertia themajor site of isotope hold-up is the transverse colon and splenic flexure. Other constipatedpatients show delay of label at a later stage and accumulation of activity in the descendingand rectosigmoid colon. Diarrhoea causes changes in the electrolyte and water content of