Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation.
OBJECTIVE
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, namely, epithelial permeability, enteric bacterial numbers, and enterohepatic recirculation, using an NSAID derivative (nitrofenac) that does not cause small intestinal damage.


METHODS
Rats were given diclofenac or nitrofenac at 12-hour intervals. Epithelial permeability to [51Cr]-ethylenediaminetetraacetic acid and enteric bacterial numbers were determined after 1-4 doses of the drugs. Serum levels and biliary excretion of the two drugs were determined by high-performance liquid chromatography.


RESULTS
Diclofenac caused a progressive increase in epithelial permeability, marked increases in enteric gram-negative bacterial 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 effect on enteric bacterial numbers and did not cause frank ulceration. Unlike diclofenac, nitrofenac did not undergo extensive enterohepatic recirculation. Two other NSAIDs that do not undergo enterohepatic recirculation (nabumetone and aspirin) also did not modify enteric bacterial numbers or cause intestinal ulceration.


CONCLUSIONS
Enterohepatic recirculation of NSAIDs is of paramount importance in the pathogenesis of enteropathy caused by these drugs, whereas suppression of prostaglandin synthesis is relatively unimportant.
Reuter
B K
BK
Intestinal Disease Research Unit, Faculty of Medicine, University of Calgary, Alberta, Canada.
Davies
N M
NM
Wallace
J L
JL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D015169:Colony Count, Microbial; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004764:Enterohepatic Circulation; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000382:microbiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; C087608:nitrofenac