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

Abstract

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 micromol/L for COX-1; IC50=4.65 micromol/L for COX-2), being approximately 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 micromol/L [COX-1] and 0.87 micromol/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.

Pharmacological characteristics of metamizole

“…For a long time, metamizole was considered to be a non-selective COX-1 and COX-2 inhibitor (Hinz et al 2007, Pierre et al 2007, Rogosch et al 2012. The mechanism involved in its analgesic effect is complex (Fig.…”

“…Unquestionably, the drug inhibits COX-3 more strongly (Chandrasekharan et al 2002). Although is has been shown that metamizole inhibits both COX-1 and COX-2 (Campos et al 1999, Hinz et al 2007, Pierre et al 2007, it is uncertain whether the effect is clinically significant because we lack a substantial body of evidence proving that this medication can cause a significant anti-inflammatory effect.…”

“…Metamizole shows a spasmolytic effect (Gulmez et al 2006, Hinz et al 2007). Gulmez et al (2006) proved the spasmolytic influence of metamizole on a guinea pig's isolated tracheal smooth muscle.…”

The Impact of Nonsteroidal Anti-inflammatory Drugs on Inflammatory Response After Aneurysmal Subarachnoid Hemorrhage

“…Based on our results, it might be assumed that acetaminophen has some effect on the inflammatory response, as the correlations of cumulative NSAID days with IL-6 and CRP were weaker without acetaminophen. Another NSAID drug that was included in the analysis was dipyrone, which has pronounced analgesic and antipyretic effects, but weak anti-inflammatory effects as well [23]. Although its mechanism of action is not entirely clear, it elicits substantial inhibition of COX in humans.…”

Dipyrone, Great Killer or Innocent as Any Drug: Two Case Reports Presenting Rare and Life-Threatening Adverse Effects of Dipyrone

“…Moreover, it is useful for the treatment of cancer pain and migraine as well as fever refractory to other treatments. 1 Dipyrone is a pro-drug that undergoes non-enzymatic hydrolysis in the stomach to form 4-methylamino-antipyrine . This active metabolite is rapidly and almost completely absorbed.…”