Biochemical and pharmacological effects of dipyrone and its metabolites in model systems related to arachidonic acid cascade.
The metabolites of dipyrone (metamizol, Novalgin) were compared with appropriate standard drugs for their influences on the pathways of the arachidonic acid metabolism. The drugs in this study had no significant effects on the lipoxygenase pathway in human neutrophils in vitro. The dipyrone metabolites 4-methylaminoantipyrine (MAAP) and 4-aminoantipyrine (AAP) inhibited prostaglandin synthesis in the 10(-3) to 10(-4) mol/l range thus being comparable to acetylsalicylic acid (ASA), whereas the two additional metabolites 4-acetylaminoantipyrine (AAAP) and 4-formylaminoantipyrine (FAAP) were practically inactive. This result is in accordance with the effects of the metabolites on the formation of oedema in the arthritis rat model, and supports published data showing that MAAP and AAP are the metabolites responsible for the clinical effects of dipyrone. Further systems in our study depending at least partially on the prostaglandin pathway were the release of antiaggregatory activity from rat aortae in vitro and the aggregation of human platelets induced by arachidonic acid in vitro. MAAP exhibits antiaggregatory activity (IC50 5 x 10(-6) mol/l), whereas the inhibitory effect on the vascular antiaggregatory release is much weaker. Compared to normals platelet aggregability ex vivo is enhanced in arthritic rats, but could significantly be lowered again by treatment of the rats with MAAP. A further system studied was the release of 6-keto-PGF1 alpha from rat mucosa in vitro and ex vivo. In vitro there is inhibition to be found with MAAP as well as with ASA. Ex vivo, however, dipyrone or MAAP slightly stimulates mucosal 6-keto-PGF1 alpha rather than inhibiting it, whereas ASA exerts inhibition, as expected.(ABSTRACT TRUNCATED AT 250 WORDS)
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000632:Aminopyrine / Q000031:analogs & derivatives*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000517:prevention & control; D001792:Blood Platelets / Q000187:drug effects; D004177:Dipyrone / Q000378:metabolism / Q000494:pharmacology*; D011464:Epoprostenol / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009504:Neutrophils / Q000201:enzymology; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D000632:Aminopyrine; D016718:Arachidonic Acid; D015121:6-Ketoprostaglandin F1 alpha; D004177:Dipyrone; D011464:Epoprostenol; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases