In vivo formation of 4-formylaminoantipyrine as a new metabolite of aminopyrine. I.

Noda, Atsuko; Goromaru, Tsuyoshi; Tsubone, Nobuo; Matsuyama, Kenji; Iguchi, Sadao

doi:10.1248/cpb.24.1502

Cited by 31 publications

(10 citation statements)

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“…MAA is converted to a variety of metabolites, including 4-formyl-amino-antipyrine (FAAP) and 4-amino-antipyrine (AA; Fig. 1), the latter being acetylated to 4-acetyl-amino-antipyrine (AAAP) by the polymorphic enzyme N-acetyl-transferase (2,3).…”

Section: Dipyrone (Inn Metamizol)mentioning

confidence: 99%

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

Hinz¹,

Cheremina²,

Bachmakov³

et al. 2007

FASEB j.

124

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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.

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Section: Dipyrone (Inn Metamizol)mentioning

confidence: 99%

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

Hinz¹,

Cheremina²,

Bachmakov³

et al. 2007

FASEB j.

124

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“…Metamizole is a Moderate Cytochrome P450 Inducer Via the Constitutive Androstane Receptor and a Weak Inhibitor of CYP1A2 Fabio Bachmann 1,2 , Urs Duthaler 1,2 , Henriette E. Meyer zu Schwabedissen 3 , Maxim Puchkov 4 , Jörg Huwyler 4 , Manuel Haschke 5,6 and Stephan Krähenbühl 1,2, * Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces cytochrome (CYP) 2B6 and possibly CYP3A4.…”

mentioning

confidence: 99%

“…Furthermore, 4-AA is acetylated by N-acetyltransferase 2 to 4-acetylaminoantipyrine, another end metabolite. [6][7][8][9][10][11][12] The metabolic pathway of metamizole is illustrated in Figure 1. The enzymes responsible for the demethylation and the oxidation of 4-MAA have so far not been conclusively identified.…”

mentioning

confidence: 99%

Metamizole is a Moderate Cytochrome P450 Inducer Via the Constitutive Androstane Receptor and a Weak Inhibitor of CYP1A2

Bachmann

Duthaler

Schwabedissen

et al. 2021

Clin Pharma and Therapeutics

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Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Several studies indicate that metamizole is an inducer of CYP2B6 and CYP3A4. However, no studies have so far been conducted to elucidate the interaction potential of metamizole for other CYPs. Furthermore, the mechanism of induction is currently not known. WHAT QUESTION DID THIS STUDY ADDRESS? This study addressed the influence of metamizole on the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 in healthy volunteers. Additionally, in vitro experiments were conducted to explore the mechanism of CYP induction.

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“…In this case, FAA is formed by formylation (formyl conjugation) of AA. Noda et al (37), however, reported that FAA is formed by oxidation of the N-methyl group of MAA. Agundez et al (31) further showed that 29% of aminopyrine is converted into FAA via MAA and found a large interindividual difference in the formation of FAA, i.e.…”

Section: -Aminopyrine Breath Testmentioning

confidence: 99%

Critical appraisal of ¹³C breath tests for microsomal liver function: aminopyrine revisited

Pijls

Vries

Nikkessen

et al. 2014

Liver International

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As liver diseases are a major health problem and especially the incidence of metabolic liver diseases like non-alcoholic fatty liver disease (NAFLD) is rising, the demand for non-invasive tests is growing to replace liver biopsy. Non-invasive tests such as carbon-labelled breath tests can provide a valuable contribution to the evaluation of metabolic liver function. This review aims to critically appraise the value of the 13 C-labelled microsomal breath tests for the evaluation of metabolic liver function, and to discuss the role of cytochrome P450 enzymes in the metabolism of the different probe drugs, especially of aminopyrine. Although a number of different probe drugs have been used in breath tests, the perfect drug to assess the functional metabolic capacity of the liver has not been found. Data suggest that both the 13 C 2 -aminopyrine and the 13 C-methacetin breath test can play a role in assessing the capacity of the microsomal liver function and may be useful in the follow-up of patients with chronic liver diseases. Furthermore, CYP2C19 seems to be an important enzyme in the N-demethylation of aminopyrine, and polymorphisms in this gene may influence breath test values, which should be kept in mind when performing the 13 C 2 -aminopyrine breath test in clinical practice.

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In vivo formation of 4-formylaminoantipyrine as a new metabolite of aminopyrine. I.

Cited by 31 publications

References 0 publications

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

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

Metamizole is a Moderate Cytochrome P450 Inducer Via the Constitutive Androstane Receptor and a Weak Inhibitor of CYP1A2

Critical appraisal of ¹³C breath tests for microsomal liver function: aminopyrine revisited

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In vivo formation of 4-formylaminoantipyrine as a new metabolite of aminopyrine. I.

Cited by 31 publications

References 0 publications

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

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

Metamizole is a Moderate Cytochrome P450 Inducer Via the Constitutive Androstane Receptor and a Weak Inhibitor of CYP1A2

Critical appraisal of 13C breath tests for microsomal liver function: aminopyrine revisited

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Critical appraisal of ¹³C breath tests for microsomal liver function: aminopyrine revisited