NONSTEROIDAL ANTIINFLAMMATORY DRUG ENTEROPATHY IN RATS - ROLE OF PERMEABILITY, BACTERIA, AND ENTEROHEPATIC CIRCULATION

Background & Aims: The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage remains poorly understood , The aim of this study was to examine the relative importance of the three suggested components of the pathogenesis of NSAID enteropathy, n amely, epithelial permeability, enteric bacterial numbers, and enteroh epatic recirculation, using an NSAID derivative (nitrofenac) that does not cause small intestinal damage. Methods: Rats were given diclofena c or nitrofenac at 12-hour intervals, Epithelial permeability to [Cr-5 1]-ethylenediaminetetraacetic acid and enteric bacterial numbers were determined after 1-4 doses of the drugs, Serum levels and biliary excr etion of the two drugs were determined by high-performance liquid chro matography, Results: Diclofenac caused a progressive increase in epith elial permeability, marked increases in enteric gram-negative bacteria l numbers, and frank intestinal ulceration, Nitrofenac caused similar changes in intestinal permeability after a single dose but no further increase with repeated administration, Moreover, nitrofenac had no eff ect on enteric bacterial numbers and did not cause frank ulceration. U nlike diclofenac, nitrofenac did not undergo extensive enterohepatic r ecirculation. Two other NSAIDs that do not undergo enterohepatic recir culation (nabumetone and aspirin) also did not modify enteric bacteria l numbers or cause intestinal ulceration, Conclusions: Enterohepatic r ecirculation of NSAIDs is of paramount importance in the pathogenesis of enteropathy caused by these drugs, whereas suppression of prostagla ndin synthesis is relatively unimportant.