Formation of 4-formylaminoantipyrine as a new metabolite of aminopyrine. II. Enzymatic demethylation and oxidation of aminopyrine and 4-monomethylaminoantipyrine.

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

“…The 4‐MAA is the major metabolite in plasma, which is demethylated to 4‐aminoantipyrine (4‐AA) or oxidized to 4‐formylaminoantipyrine, an end metabolite. Furthermore, 4‐AA is acetylated by N‐acetyltransferase 2 to 4‐acetylaminoantipyrine, another end metabolite 6–12 . The metabolic pathway of metamizole is illustrated in Figure .…”

“…Furthermore, 4-AA is acetylated by N-acetyltransferase 2 to 4-acetylaminoantipyrine, another end metabolite. [6][7][8][9][10][11][12] The metabolic pathway of metamizole is illustrated in Figure 1. The enzymes responsible for the demethylation and the oxidation of 4-MAA have so far not been conclusively identified.…”

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

“…Both our in vitro and in vivo experiments showed that CYP1A2 is the dominant enzyme for the demethylation of 4-MAA to 4-AA but also for the conversion of 4-MAA to 4-FAA. 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].…”

“…La Du et al showed that 4-MAA can be demethylated by isolated rabbit microsomes in a reaction using NADPH, Mg 2+ and oxygen and producing formaldehyde, but this reaction accounted for less than 50% of 4-MAA degradation [20]. Twenty years after the publication of La Du et al, Noda et al demonstrated that the oxidative conversion of 4-MAA to 4-FAA accounted for most of the microsomal activity that had not been identified by La Du et al [21,22]. In support of these findings, Geisslinger et al verified that 4-MAA could be converted to 4-AA at a slow rate by human liver microsomes [23].…”

Challenges of HPLC method development and validation for the assay of combined drug products

“…An additional benefit is that its administration does not require specially trained staff. Agranulocytosis, one of the registered side-effects of the substance, has a very low incidence, while carcinogenicity, another possible side-effect, can be completely eliminated through rectal administration [27][28][29][30][31][32][33][34][35]. During its biotransformation, AMFZ is demethylated in two steps, catalysed by cytochrome P450 2B [28,29].…”