Comparative effects of some non-steroidal anti-inflammatory drugs on the ultrastructural integrity and prostaglandin levels in the rat gastric mucosa: relationship to drug uptake.

Studies were performed in fasted rats to establish if the propensity of 4 non-steroidal anti-inflammatory (NSAI) drugs to elicit varying degrees of gastric mucosal damage following oral administration is related to their rate of absorption by the mucosal and subsequent inhibitory effects on prostaglandin (PG) production in vivo. Aspirin (200 mg/kg p.o.) and indomethacin (10 mg/kg p.o.) produced ultrastructural signs of damage at 10-60 min to the surface mucous cells, parietal cells and endothelial cells of sub-mucosal capillaries coincident with the relatively rapid absorption of the radiolabelled drugs and reduction in the mucosal content of PGE2 and 6-keto PGF1 alpha determined by gas chromatography/mass spectrometry. Azapropazone (100 mg/kg p.o.) failed to elicit mucosal damage either ultrastructurally or even visually up to 23 h after dosing and did not affect the content of PG's even though the drug was present in the mucosa in sufficient concentration to elicit reduction in prostaglandin synthesis in vitro. Benoxaprofen (110 mg/kg p.o.) reduced the content of PGE2 and somewhat variably, that of 6-keto PGF1 alpha, was more slowly absorbed c.f. aspirin and indomethacin, but failed to elicit appreciable mucosal damage. These results show that while reduction in PG synthesis is a factor in the development of damage by ulcerogenic drugs, it appears that the rate of absorption or other biochemical effects (including e.g. influences on the production of oxyradicals or 5-lipoxygenase products of eicosanoid metabolism) may contribute to the relatively low irritancy of drugs such as azapropazone or benoxaprofen.