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