Effect of anti-inflammatory and analgesic pyrazoles on arachidonic acid metabolism in isolated heart and gastric mucosa preparations.

The effects of acidic and nonacidic pyrazoles on the release of arachidonic acid-derived mediators from isolated perfused anaphylactic guinea pig hearts as well as rat and human gastric mucosa were investigated. High concentrations of the acidic drugs phenylbutazone and oxyphenbutazone as well as of the nonacidic metabolites of metamizol, i.e. 4-methylaminoantipyrine and 4-aminoantipyrine, inhibited the release of the cyclo-oxygenase products of arachidonic acid metabolism, TXB2 and 6-keto-PGF1 alpha, and simultaneously increased the release of LTC4-like immunoreactivity in hearts. By contrast, comparatively high concentrations of the metamizol metabolites 4-formylaminoantipyrine and 4-acetylaminoantipyrine were without effect. The comparable effects of acidic and nonacidic pyrazoles on eicosanoid release from anaphylactic hearts support the concept that hypersensitivity reactions to NSAIDs are related to their effect on arachidonic acid metabolism. The anti-inflammatory effects of phenylbutazone and oxyphenbutazone and of high concentrations of metamizol seem to be correlated with the inhibition of cyclo-oxygenase. On the other hand, lower concentrations of metamizol, which have analgesic and anti-pyretic effects, only marginally inhibit cardiac cyclo-oxygenase. It remains to be investigated whether the partial inhibition of the synthesis of PGI2, a major hyperalgesiccyclo-oxygenase product of arachidonic acid metabolism, at lower concentrations of the active metamizol metabolites contributes to the analgesic effect of metamizol. The acidic NSAID mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) had no effect on the cardiac release of arachidonic acid-derived cyclo-oxygenase and lipoxygenase products. The anti-inflammatory effect of these compounds requires further investigation. In isolated gastric mucosa, the active metabolite of metamizol 4-methylaminoantipyrine was found to inhibit fatty acid cyclo-oxygenase dose-dependently. Pharmacokinetic differences due to the nonacidic structure of metamizol and its metabolites as compared to acidic NSAIDs may be responsible for the fact that metamizol is better tolerated than e.g. indomethacin. In rat experiments, phenylbutazone was found to inhibit gastric mucosal cyclo-oxygenase like indomethacin. On the other hand, mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) did not affect gastric mucosal synthesis of 6-keto-PGF1 alpha. This lack of effect on gastric mucosal cyclo-oxygenase seems to be correlated with the considerably lower gastric toxicity of mofebutazone as compared to phenylbutazone.