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

AIMS: Metamizole (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. 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 male subjects. RESULTS: The 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). CONCLUSION: CYP1A2 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.