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

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 B-2 formation and lipopolysaccharide-induced prostaglandin E-2 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 mu mol/ L for COX-1; IC50 = 4.65 mu mol/ L for COX-2), being similar to 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 mu mol/ L [COX-1] and 0.87 mu mol/ 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.