The aim of this study is to identify human cytochrome P-450 enzyme (CYP) mediating
the oxidative N-demethylation of 4-methylaminoantipyrine (4-MAA) to 4-amino-antipyrine (4-AA).
The contribution of human CYP to the metabolism of 4-MAA to 4-AA in human was investigated by
using virus expressed human CYP, human liver microsomes and rat liver microsomes with chemical
inhibition studies. The substrate of 4-methylaminantipyrine was employed at five different
concentrations (12.5, 23, 46, 115 and 230 µmol/l) with varying concentrations of selective inhibitors
of CYP (CYP1A2), (CYP3A4), (CYP2C8), (CYP2A6), (CYP2D6), (CYP2C19) and (CYP1A1). 4-
MAA and 4-AA were analyzed by HPLC and enzyme kinetic parameters (Km and Vmax) were
calculated from the concentration data. The transformation of 4-methylaminoantipyrine to 4-
aminoantipyrine by microsomes prepared from baculovirus-expressed human CYP was pronounced
with CYP2C19. Metabolism of 4-methylaminoantipyrine by human liver microsomes and rat liver
microsomes was strongly inhibited by tranylcypromine, fluvoxamine and omeprazole inhibition was
observed with other CYP selective inhibitors. 4-methyl-aminoantipyrine was also evaluated as a
CYP substrate in rat liver microsomes. No significant inhibition of CYP1A2, CYP1A1, CYP3A4,
CYP2C9, CYP2D6, CYP2A6 and CYP2E1 was observed in experiments (IC50 > 269.14 µM) but
IC50 for CYP2C19 was 68.48 µM. In conclusion, the enzyme CYP2C19 apparently has an important
role in N-demethylation of 4- methylaminoantipyrine.
Keywords: Metamizole, 4-methylaminoantipyrine, 4-aminoantipyrine (4-AA), metabolism, CYP2C19.

download pdf button 11