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Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic

Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany

¹Correspondence: Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany. E-mail: hinz{at}pharmakologie.uni-erlangen.de

Dipyrone (INN, metamizol) is a common analgesic used worldwide. Its widespread prescription or over-the-counter use in many countries (e.g., Brazil, Israel, Mexico, Russia, Spain) requires insight into its mode of action. This study therefore addressed the impact of its metabolites 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA) on peripheral cyclooxygenases (COX). Pharmacokinetics of metabolites and ex vivo COX inhibition were assessed in five volunteers receiving dipyrone at single oral doses of 500 or 1000 mg. Coagulation-induced thromboxane B₂ formation and lipopolysaccharide-induced prostaglandin E₂ synthesis were measured in vitro and ex vivo in human whole blood as indices of COX-1 and COX-2 activity. In vitro, metabolites elicited no substantial COX-1/COX-2 selectivity with MAA (IC₅₀=2.55 µmol/L for COX-1; IC₅₀=4.65 µmol/L for COX-2), being 8.2- or 9-fold more potent than AA. After administration of dipyrone, MAA plasma concentrations remained above the IC₅₀ values for each isoform for at least 8 h (500 mg) and 12 h (1000 mg) postdose. COX inhibition correlated with MAA plasma levels (ex vivo IC₅₀ values of 1.03 µmol/L [COX-1] and 0.87 µmol/L [COX-2]). By contrast, plasma peak concentrations of AA after the 1000 mg dose were 2.8- and 6.5-fold below its IC₅₀ values for COX-1 and COX-2, respectively. Maximal inhibitions of COX-1 and COX-2 were 94% and 87% (500 mg), 97% and 94% (1000 mg). Taken together, dipyrone elicits a substantial and virtually equipotent inhibition of COX isoforms via MAA. Given the profound COX-2 suppression by dipyrone, which was considerably above COX-2 inhibition by single analgesic doses of celecoxib and rofecoxib, a significant portion of its analgesic action may be ascribed to peripheral mechanisms. In view of the observed COX-1 suppression, physicochemical factors (lack of acidity) rather than differential COX-1 inhibition may be responsible for dipyrone’s favorable gastrointestinal tolerability compared with acidic COX inhibitors.—Hinz, B., Cheremina, O., Bachmakov, J., Renner, B., Zolk, O., Fromm, M. F., Brune, K. Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic.

Key Words: dipyrone metabolites • human whole blood assay • pharmacokinetics