title: Comparison of the intestinal toxicity of celecoxib, a selective COX-2 inhibitor, and indomethacin in the experimental rat.
abstract: BACKGROUND
  It is suggested that the gastrointestinal toxicity of conventional non-steroid anti-inflammatory drugs (NSAIDs) is due to a 'topical' effect in addition to inhibition of the mucosal constitutive cyclo-oxygenase-1 (COX-1) enzyme. COX-2 selective inhibitors have been shown to have excellent gastrointestinal tolerability, but it is not known whether this is due to their selectivity and/or a lack of a 'topical' effect. We assessed the effects of celecoxib (a highly selective COX-2 inhibitor) on key pathophysiologic events in NSAID enteropathy.
  
  
  METHODS
  The 'topical' effects of indomethacin and celecoxib were assessed in vitro (coupled mitochondrial respiration) and in vivo (mitochondrial electron microscopy) and the consequences by study of intestinal permeability (51-Cr-labelled ethylenediamine-tetraacetic acid urinary excretion) and inflammation. We also assessed intestinal prostanoid levels (prostaglandin E, PGE) and the propensity of the drugs to induce intestinal ulcers.
  
  
  RESULTS
  Indomethacin uncoupled mitochondrial oxidative phosphorylation in vitro and in vivo, caused a significant (P < 0.0001) increase in intestinal permeability, caused mucosal inflammation and a 90% decline in intestinal PGE levels, and was associated with multiple small intestinal ulcers. Celecoxib caused no significant increase in any of these parameters, did not decrease intestinal PGE levels, and caused no intestinal ulcers.
  
  
  CONCLUSIONS
  The intestinal tolerability of celecoxib appears to be due to a combination of the absence of a 'topical' damaging effect and selective COX inhibition.
authors.affiliation: Dept. of Medicine, Guy's, Kings, St Thomas' Medical School, London, England.
authors.forename: J A
authors.initials: JA
authors.lastname: Tibble
authors.forename: G
authors.initials: G
authors.lastname: Sigthorsson
authors.forename: R
authors.initials: R
authors.lastname: Foster
authors.forename: I
authors.initials: I
authors.lastname: Bjarnason
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity*; D000068579:Celecoxib; D002463:Cell Membrane Permeability / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D004195:Disease Models, Animal; D007213:Indomethacin / Q000494:pharmacology / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D011458:Prostaglandins E / Q000032:analysis; D011720:Pyrazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000494:pharmacology / Q000633:toxicity*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011458:Prostaglandins E; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D007213:Indomethacin