The enterohepatic circulation of some anti-inflammatory drugs may cause intestinal ulcerations

Abstract

Aspirin is known to be an active ulcerogen which regularly damages the stomach mucosa. The more modern non-steroidal anti-inflammatory drugs (NSAIDs) are much less ulcerogenic, at least to the stomach mucosa. These compounds, however, still cause lesions of the small intestine ranging from irritation to ulceration and perforation. Recently, public interest has focused on these side-effects following the introduction of a controlled-release form of indomethacin. Although it remains a matter of speculation whether sufficient evidence of an enhanced ulcerogenic potential of this preparation has been collected (see Inman, Chapter 7 in this volume) it can be assumed that this preparation may indeed have caused more irritation of the small intestine than similar doses of indomethacin in standard preparations. Since indomethacin is known to undergo enterohepatic circulation in man^1,2 one would assume that, at least in some patients, sustained absorption and prolonged enterohepatic circulation of indomethacin after administration of Osmosin^R may have led to duodenal and jejunal mucosal damage following an almost constant diffusion of indomethacin through this mucosa, along with lasting inhibition of prostaglandin synthesis. Support for this interpretation may be found in published literature which shows that the AUC after some sustained-release preparations of indomethacin is indeed larger than the AUC following standard preparations containing the same dose³. Further support may be derived from literature which shows that, for a given species, the greater the degree of enterohepatic circulation of indomethacin, the more prone this species is to ulcerations of the small intestine². Furthermore if one calculates a ‘therapeutic index’ by dividing the dosage which leads to intestinal ulceration by the dosage inhibiting the carrageenan oedema in rats, and one plots this index against the degree of enterohepatic circulation of the active compound in rats, a correlation can be observed, as shown in Figure 1. This indicates that drugs displaying little enterohepatic circulation due to rapid metabolic inactivation (diclofenac, ibuprofen) or other unknown reasons (aspirin) are indeed much less damaging to the intestinal mucosa than for example indomethacin.