Structural damage and changes in eicosanoid metabolites in the gastric mucosa of rats and pigs induced by anti-inflammatory drugs of varying ulcerogenicity.
The object of the studies reviewed here has been to correlate the time-course of ultrastructural changes induced by oral administration of a range of non-steroidal anti-inflammatory (NSAI) drugs with effects on eicosanoid metabolism and drug absorption, so as to discriminate what biochemical/cellular and pharmacological factors account for their varying ulcerogenicity. Oral administration of highly ulcerogenic drugs (e.g. aspirin, diclofenac, indomethacin, piroxicam) to rats causes rapid damage to surface and gastric mucous cells, selective parietal cell damage, and extensive disruption of endothelial cells of submucosal microcapillaries (especially with aspirin) with accompanying extravasation of blood cell components. These changes are coincident with depressed levels of PGE2/6-keto-PGF1 alpha (measured by GC/MS or RIA) and uptake of the drugs (measured by scintillation counting or HPLC). Low ulcerogenic NSAI drugs (e.g. azapropazone, benoxaprofen and fenclofenac) causes very little damage to the surface mucosal cells. Azapropazone has been found to be well absorbed, and benoxaprofen and fenclofenac somewhat more slowly, so for the latter two drugs their low rate of absorption might also be a factor in their reduced ulcerogenicity. Aspirin, azapropazone and benoxaprofen have been shown to reduce 5-HETE levels (RIA), although the latter two drugs were more effective than aspirin. Thus, they result in the inhibition of PG production, by cyclo-oxygenase inhibition (with potential adverse effects from excess oxyradical and/or production of HETE's) with inhibition of the lipoxygenase pathway. The time-sequence of changes induced by single oral doses of indomethacin or other NSAI drugs on the ultrastructure and the prostanoid metabolism of the pig gastric mucosa parallelled those seen in the rat. Attempts to determine whether co-administration of NSAI drugs might reduce the inhibition of PG cyclo-oxygenase by more potent inhibitors (e.g. indomethacin) have been explored as a means for reducing the gastric ulcerogenicity of the latter. The results suggest that pharmacokinetic factors may largely account for the reduced ulcerogenicity of these drug mixtures.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000633:toxicity*; D001241:Aspirin / Q000633:toxicity; D004061:Diflunisal / Q000633:toxicity; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D007213:Indomethacin / Q000633:toxicity; D008564:Membrane Potentials / Q000187:drug effects; D008854:Microscopy, Electron; D010648:Phenylacetates / Q000633:toxicity; D010894:Piroxicam; D011422:Propionates / Q000633:toxicity; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced / Q000378:metabolism*; D013467:Sulindac / Q000633:toxicity; D013552:Swine; D013843:Thiazines / Q000633:toxicity
D000893:Anti-Inflammatory Agents; D010648:Phenylacetates; D011422:Propionates; D011453:Prostaglandins; D013843:Thiazines; D010894:Piroxicam; C011677:benoxaprofen; D013467:Sulindac; D004061:Diflunisal; D001241:Aspirin; D007213:Indomethacin; C012970:fenclofenac