Pyrazolones metabolites are relevant for identifying selective anaphylaxis to metamizole

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common cause of hypersensitivity reactions, with pyrazolones the most frequent drugs inducing selective reactions. Immediate selective hypersensitivity to pyrazolones is thought to be mediated by specific-IgE. Sensitivity of in vitro diagnostic tests is low and this may be due to the incomplete characterization of the structures involved. Here we investigated whether main metabolites of metamizole (dipyrone) in human could be involved in the immune response using the basophil activation test (BAT). We studied subjects with confirmed selective immediate hypersensitivity to metamizole and performed BAT with metamizole and its metabolites: 4-methylamino-antipyrine (MAA), 4-aminoantipyrine (AA), 4-acetylamino-antipyrine (AAA) and 4-formylamino-antipyrine (FAA). BAT results showed an increase of positive results from 37.5% to 62.5% using metamizole plus metabolites as compared with the BAT carried out only with the parent drug, demonstrating that metamizole metabolites have a role in the reaction and can induce specific basophil activation in patients with immediate hypersensitivity to this drug. Our findings indicate that pyrazolone metabolites are useful for improving the in vitro diagnosis of allergic reactions to metamizole.

Characteristics of NSAID‐induced hypersensitivity reactions in childhood

“…In order to elucidate immunologically mediated reactions, NSAIDs are metabolized into their active metabolites that bind to the serum or cellular proteins . Pyrazolones are one of the main groups of NSAIDs emerging IgE‐mediated reactions, and metamizole metabolites were shown to induce basophil activation in patients with selective immediate‐type reactions to metamizole . Propionic acid derivatives compose another group of NSAIDs resulting in selective immediate‐type reactions .…”

Metamizole (Dipyrone) and the Liver: A Review of the Literature

“…As the first active metabolite of metamizole, 4‐MAA reaches its peak plasma concentration within 1 to 2 hours and is further metabolized in the liver to both a second active metabolite, 4‐aminoantipyrine (4‐AA), via N‐demethylation, and a first inactive metabolite, 4‐formylaminoantipyrine (4‐FAA), via C‐oxidation . Up to now, hepatic metabolism of 4‐MAA was known to be mediated by the cytochrome P450 (CYP) 3A4 system .…”

“…Compared to 4‐MAA, 4‐AA as the second active metabolite of metamizole has a markedly weaker analgesic effect and a longer time to peak plasma concentration, but a longer pharmacological half‐life. The combination of these properties of 4‐MAA and 4‐AA is leading to both the fast and long‐lasting efficacy of metamizole . Further metabolization of 4‐AA to another inactive metabolite, 4‐acetylaminoantipyrine (4‐AAA), via acetylation is mediated by a polymorphic N‐acetyltransferase system .…”

“…Results of an in vitro study performed by Lüthy et al suggest that metamizole does not inhibit cyclooxygenase by binding covalently to the enzyme. On the contrary, Ariza et al recently could establish a basophil activation test to identify selective anaphylaxis for metamizole and its metabolites and assumed that molecules inducing such reaction require covalent binding to plasma proteins . Furthermore, several trials found strong evidence that development of the metamizole‐induced agranulocytosis mentioned above is mediated by drug‐dependent antineutrophil antibodies requiring covalent binding of the drug or its metabolites to neutrophils …”

“…However, an increasing number of side effects of metamizole have been reported over the following decades affecting the cardiovascular system (ie, hypotension and arrhythmia), the respiratory system (ie, bronchospasm, especially in asthmatic patients), and the skin (ie, maculopapular rash), among others . While most of these side effects rapidly disappear after discontinuation of the drug and/or are manageable in a clinical setting, metamizole‐induced agranulocytosis, whose first description dates back to 1936, poses a serious threat to the patient's life .…”