RECTAL ABSORPTION ENHANCEMENT OF PEPTIDE DRUGS

There are various reasons for rectal drug administration. Two of the most obvious ones are situations when patients are vomiting or suffering from nausea, while it has also been shown that it is possible to avoid at least partially hepatic first-pass elimination following rectal administration. An additional reason is the fact that the rectum environment is quite constant with respect to pH; composition, volume and viscosity of fluid; and less influenced by food. This offers the opportunity for rate controlled rectal drug delivery. Indeed it has been shown for various drugs e.g. antipyrine, theophylline, midazolam, lidocaine, nifedipine etc., that rate-controlled rectal drug administration is well possible. For hydrophilic drugs the rectal mucosa acts as a physical barrier and absorption enhancers can be applied to increase the extent and rate of absorption. Various enhancers can be used, NSAID's, bile salts, surfactants, STDHF, fatty acids, mono-, di- and triglycerides, enamines, mixed micelles etc., their mechanisms of action mostly being not fully elucidated, to increase trans- and/or paracellular transport of drug. Increased absorption of drugs has been demonstrated depending also on the rate of administration. In addition, increased absorption of peptides e.g. DEyE and DGAVP and proteins such as insulin, albumin, somostatin analogue, has been accomplished. However, one of the major concerns, tissue and/or membrane damage, especially following repeated application, has not been dealt with satisfactorily. Detailed information about mechanisms of absorption enhancement and of membrane or tissue damage is needed to optimize drug absorption enhancement and reduce damage to at least acceptable levels. For hydrophylic drugs, especially peptides and proteins, the rectal mucosa acts not only as a physical barrier but also as a metabolic barrier. Therefore to increase the extent of absorption of these drugs absorption enhancers and metabolic inhibitors should be applied. This on its turn stresses the need of a careful tuning of the administration of enhancer, inhibitor and drug to obtain the optimum rate and extent of absorption. © 1990.