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Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine
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  • Fabio Bachmann,
  • Urs Duthaler,
  • Henriette Meyerzuschwabidissen,
  • Stephan Krahenbuhl
Fabio Bachmann
Universitat Basel Departement Biomedizin
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Urs Duthaler
University Hospital Basel
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Henriette Meyerzuschwabidissen
University of Basel
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Stephan Krahenbuhl
University Hospital
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Abstract

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.

Peer review status:IN REVISION

24 Jun 2021Submitted to British Journal of Clinical Pharmacology
25 Jun 2021Submission Checks Completed
25 Jun 2021Assigned to Editor
04 Jul 2021Reviewer(s) Assigned
11 Aug 2021Review(s) Completed, Editorial Evaluation Pending
12 Aug 2021Editorial Decision: Revise Major
10 Sep 20211st Revision Received
14 Sep 2021Submission Checks Completed
14 Sep 2021Assigned to Editor
14 Sep 2021Review(s) Completed, Editorial Evaluation Pending
23 Sep 2021Editorial Decision: Revise Minor