Trial reportBritish journal of clinical pharmacology2022
Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine.
Trial report in British journal of clinical pharmacology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 11 citations in OpenAlex.
- Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine.British journal of clinical pharmacology · 2022Trial
- Influence of Tramadol on the Intravenous Pharmacokinetics of Dipyrone Active Metabolites in Dogs.Journal of veterinary pharmacology and therapeutics · 2026Article
- Pharmacokinetic Profile of Two Active Dipyrone Metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), Following Intravenous Administration in Dogs: A Preliminary Study.Animals : an open access journal from MDPI · 2025Article
- A probable case of metamizole-induced neutropaenia presenting 10 days after drug discontinuation.SAGE open medical case reports · 2025Article
- The Effect of Epidural Analgesia on Quality of Recovery (QoR) after Open Radical Nephrectomy: Randomized, Prospective, and Controlled Trial.Journal of personalized medicine · 2024Article
- Article
- Pharmacogenetic Analysis of Voriconazole Treatment in Children.Pharmaceutics · 2022Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsMetamizole (dipyrone) is a prodrug not detectable in serum or urine after oral ingestion. The primary metabolite, 4-methylaminoantipyrine (4-MAA), can be N-demethylated to 4-aminoantipyrine (4-AA) or oxidized to 4-formylaminoantipyrine (4-FAA) by cytochrome P450 (CYP)-dependent reactions. We aimed to identify the CYPs involved in 4-MAA metabolism and to quantify the effect of CYP inhibition on 4-MAA metabolism.
methodsWe investigated the metabolism of 4-MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in male subjects.
resultsThe experiments in supersomes revealed CYP1A2 as the major CYP for 4-MAA N-demethylation and 4-FAA formation with CYP2C19 and CYP2D6 contributing to N-demethylation. In the clinical study, we investigated the influence of ciprofloxacin (CYP1A2 inhibitor), fluconazole (CYP2C19 inhibitor) and the combination ciprofloxacin/fluconazole on the pharmacokinetics of metamizole in n = 12 male subjects in a randomized, placebo-controlled, double-blind study. The geometric mean ratios for the area under the concentration-time curve of 4-MAA after/before treatment were 1.17 (90% CI 1.09-1.25) for fluconazole, 1.51 (90% CI 1.42-1.60) for ciprofloxacin and 1.92 (90% CI 1.81-2.03) for ciprofloxacin/fluconazole. Fluconazole increased the half-life of 4-MAA from 3.22 hours by 0.47 hours (95% CI 0.13-0.81, P < .05), ciprofloxacin by 0.69 hours (95% CI 0.44-0.94, P < .001) and fluconazole/ciprofloxacin by 2.85 hours (95% CI 2.48-3.22, P < .001).
conclusionCYP1A2 is the major CYP for the conversion of 4-MAA to 4-AA and 4-FAA. The increase in 4-MAA exposure by the inhibition of CYP1A2 and by the combination CYP1A2/CYP2C19 may be relevant for dose-dependent adverse reactions of 4-MAA.
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