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The primary metabolite, 4\u2010methylaminoantipyrine (4\u2010MAA), can be N\u2010demethylated to 4\u2010aminoantipyrine (4\u2010AA) or oxidized to 4\u2010formylaminoantipyrine (4\u2010FAA) by cytochrome P450 (CYP)\u2010dependent reactions. We aimed to identify the CYPs involved in 4\u2010MAA metabolism and to quantify the effect of CYP inhibition on 4\u2010MAA metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the metabolism of 4\u2010MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in male subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The experiments in supersomes revealed CYP1A2 as the major CYP for 4\u2010MAA N\u2010demethylation and 4\u2010FAA formation with CYP2C19 and CYP2D6 contributing to N\u2010demethylation. 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 <jats:italic>n\u2009=<\/jats:italic>\u00a012 male subjects in a randomized, placebo\u2010controlled, double\u2010blind study. The geometric mean ratios for the area under the concentration\u2013time curve of 4\u2010MAA after\/before treatment were 1.17 (90% CI 1.09\u20131.25) for fluconazole, 1.51 (90% CI 1.42\u20131.60) for ciprofloxacin and 1.92 (90% CI 1.81\u20132.03) for ciprofloxacin\/fluconazole. Fluconazole increased the half\u2010life of 4\u2010MAA from 3.22\u2009hours by 0.47\u2009hours (95% CI 0.13\u20130.81, <jats:italic>P<\/jats:italic> &lt;\u2009.05), ciprofloxacin by 0.69\u2009hours (95% CI 0.44\u20130.94, <jats:italic>P<\/jats:italic> &lt;\u2009.001) and fluconazole\/ciprofloxacin by 2.85\u2009hours (95% CI 2.48\u20133.22, <jats:italic>P<\/jats:italic> &lt;\u2009.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CYP1A2 is the major CYP for the conversion of 4\u2010MAA to 4\u2010AA and 4\u2010FAA. The increase in 4\u2010MAA exposure by the inhibition of CYP1A2 and by the combination CYP1A2\/CYP2C19 may be relevant for dose\u2010dependent adverse reactions of 4\u2010MAA.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15108","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T13:23:28Z","timestamp":1634217808000},"page":"1885-1896","source":"Crossref","is-referenced-by-count":11,"title":["Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4\u2010methylaminoantipyrine"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2789-4377","authenticated-orcid":false,"given":"Fabio","family":"Bachmann","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology &amp; Toxicology University Hospital  Basel Switzerland"},{"name":"Department of Clinical Research University of Basel  Switzerland"},{"name":"Department of Biomedicine University of Basel  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0458-4579","authenticated-orcid":false,"given":"Henriette E.","family":"Meyer zu Schwabedissen","sequence":"additional","affiliation":[{"name":"Biopharmacy, Department of Pharmaceutical Sciences University of Basel  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-3932","authenticated-orcid":false,"given":"Urs","family":"Duthaler","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology &amp; 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