English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

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.

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