TOXICOKINETICS OF INDOMETHACIN-INDUCED INTESTINAL PERMEABILITY IN THERAT

Numerous studies in humans have demonstrated increases in intestinal p ermeability resulting from the administration of non-steroidal anti-in flammatory drugs (NSAIDs). The increased permeability correlates well with ulceration. The time course of the changes in intestinal permeabi lity, however, has not been studied, which makes comparative studies b etween different NSAIDs or different formulations of the same drug dif ficult. In the present study we have administered single doses of indo methacin to examine both the time course and pharmacokinetic/pharmacod ynamic relationships of intestinal permeability in rats estimated by f ollowing the urinary excretion of [Cr-51]-EDTA. The change in intestin al permeability was both time-and dose-dependent. Following both 10 mg kg(-1) and 20 mg kg(-1) oral doses of indomethacin, there was a rapid rise in intestinal permeability to a maximum level, after at least 12 h post-dose, which is longer than those previously observed for ibupr ofen, ketoprofen, flurbiprofen and naproxen. The maximal effect lasted 12 and 36 h following 10 and 20 mg kg(-1) doses, respectively. The si de-effect-plasma concentration relationship demonstrated a counter-clo ckwise hysteresis. The relationship between the observed side-effect a nd the estimated deep effect compartment concentration was, on the oth er hand, linear. In comparative permeability studies of NSAIDs the tim e of administration, concentration and drug dependencies should be con sidered. (C) 1997 The Italian Pharmacological Society.