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

Bachmann, Fabio; Duthaler, Urs; Schwabedissen, Henriette E. Meyer zu; Puchkov, Maxim; Haschke, Manuel; Krähenbühl, Stephan

doi:10.1002/cpt.2141

Cited by 27 publications

(44 citation statements)

References 53 publications

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“…So far, it had been demonstrated that both reactions are catalyzed by hepatic microsomes [22][23][24] but the CYPs involved had not been clearly identified and verified in a clinical study. The results of the current study are in agreement with those in a recent study where we investigated the effect of metamizole on the activity of different CYPs [30]. In this study, we found that metamizole inhibits the conversion of caffeine to paraxanthine, which is catalyzed by CYP1A2, most likely in a competitive fashion.…”

Section: Discussionsupporting

confidence: 92%

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Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine

Bachmann

Duthaler

Meyerzuschwabidissen

et al. 2021

Preprint

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Aim: Metamizole (dipyrone) is a prodrug not detectable in serum or urine after oral ingestion. The primary metabolite is 4-methylaminoantipyrine (4-MAA), which can be N-demethylated to 4-aminoantipyrine (4-AA) or oxidized to 4-formylaminoantipyrine (4-FAA) by cytochrome P450 (CYP)-dependent reactions. Our aim was to identify the CYPs involved. Methods: We investigated the metabolism of 4-MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in healthy volunteers. Results: The experiments in supersomes revealed CYP1A2 as the major CYP for 4-MAA N-demethylation and 4-FAA formation. CYP2C19 and CYP2D6 contributed to N-demethylation but not to FAA formation. In the subsequent clinical study, we investigated the influence of ciprofloxacin (strong CYP1A2 inhibitor), fluconazole (strong CYP2C19 inhibitor) and the combination ciprofloxacin/fluconazole on the pharmacokinetics of a single dose of metamizole in n=12 healthy volunteers in a randomized, placebo-controlled, double-blind study. Both ciprofloxacin and fluconazole inhibited the metabolism of 4-MAA, confirming the in vitro results. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the AUC0-12h of 4-MAA by 51%, 17% and 92%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole decreased the AUC0-12h of 4-AA by 27%, 12% and 24%, respectively, and of 4-FAA by 33%, 9% and 51%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the half-life of 4-MAA from 3.22 h (placebo) to 3.91, 3.69 and 6.07 h, respectively. Conclusion: CYP1A2 is the major CYP for the conversion of 4-MAA to 4-AA and 4-FAA. CYP1A2 inhibition increases the 4-MAA exposure by a factor of approximately 1.5, which could be relevant for dose-dependent adverse reactions.

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Section: Discussionsupporting

confidence: 92%

“…The genotypes of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2D6 were assessed as published previously [25].…”

Section: Genotypingmentioning

confidence: 99%

Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine

Bachmann

Duthaler

Meyerzuschwabidissen

et al. 2021

Preprint

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“…The samples for the analysis were obtained from a previously published clinical study. 14 The study (clinicaltrials.gov, ID: Single nucleotide polymorphisms for CYP1A2, CYPB6, CYP2C9, CYP2C19 and CYP2D6 have been assessed and are given in the supplement (Table S1).…”

Section: Clinical Studymentioning

confidence: 99%

“…The Basel phenotyping cocktail consists of 6 different substrates specific for 6 CYP isoforms (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A4: midazolam) 13 and has been safely applied for phenotyping in humans. 6,[13][14][15][16] Regarding the employed substrates, it becomes evident that glucuronidation might also be important for the metabolism of other phenotyping substrates than midazolam. For instance, 8 0 -hydroxyefavirenz 17 as well 4 0 -hydroxyflurbiprofen are known to be glucuronidated.…”

Section: Introductionmentioning

confidence: 99%

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Effect of deglucuronidation on the results of the Basel phenotyping cocktail

Bachmann

Duthaler

Krähenbühl

2021

Brit J Clinical Pharma

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We investigated the effect of deglucuronidation on the plasma concentration of the constituents of the Basel phenotyping cocktail and on the interpretation of the phenotyping results under basal conditions and after cytochrome P450 (CYP) induction with metamizole. The cocktail containing caffeine (CYP1A2), efavirenz (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6) and midazolam (CYP3A4) was administered to 12 healthy subjects before (basal) and after treatment with metamizole for 1 week. In the basal state, deglucuronidation caused an increase in the plasma concentrations and area under the curve (AUC) of metoprolol, 8′‐hydroxyefavirenz, 4′‐hydroxyflurbiprofen and 1′‐hydroxymidazolam. This effect could be visualized in Bland–Altman plots, where the values for 8′‐hydroxyefavirenz, 4′‐hydroxyflurbiprofen and 1′‐hydroxymidazolam were mostly above the +20% threshold. As a result, the metabolic ratio (MR), calculated as AUCparent drug/AUCmetabolite, decreased with deglucuronidation for CYP2B6, CYP2C9 and CYP3A4 and increased for CYP2D6. Treatment with metamizole, a constitutive androstane receptor‐dependent inducer of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, accentuated the effect of deglucuronidation on AUC and MR. The correlation of MRs calculated as the plasma concentration ratio parent drug/metabolite with the MR calculated as the AUC ratio showed that 1 sample obtained between 2 and 6 hours after cocktail ingestion and analysed with and without deglucuronidation is sufficient to obtain reliable phenotyping results. Importantly, CYP2C9 and 3A4 induction would have been missed without deglucuronidation of the plasma samples. In conclusion, deglucuronidation of the plasma samples improves the stability of the phenotyping results of the Basel phenotyping cocktail and is necessary to reliably detect CYP induction.

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The Uncertainties of Metamizole Use

Cascorbi

2021

Clin Pharma and Therapeutics

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

Cited by 27 publications

References 53 publications

Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine

Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine

Effect of deglucuronidation on the results of the Basel phenotyping cocktail

The Uncertainties of Metamizole Use

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