Pharmacogenetic determinants of human liver microsomal aminopyrine metabolism and the role of cytochrome P450 2D6
Aminopyrine (AM) has been used as a model substrate for investigation of drug metabolism. The
major metabolic route is N-demethylation that was confirmed in liver microsomes. The aim of the present
study was to identify the human cytochrome P-450 enzyme (CYP) mediating the N-demethylation of 4-dimethylaminoantipyrine
(4-DMAA) to 4-methylaminoantipyrine (4-MAA). The contribution of human CYP
to the metabolism of (4-DMAA) to (4-MAA) in human was investigated using virus expressed human CYP,
human liver microsomes with chemical inhibition studies. The substrate of 4-dimethylaminantipyrine was
employed at different concentrations (11.5, 23, 46, 115 and 230 μmol per l) with varying concentrations of
selective inhibitors of CYP (CYP1A2), (CYP3A4), (CYP2C8),(CYP2A6), (CYP2D6), (CYP2C19) and
(CYP1A1). 4-DMAA and 4-MAA were analysed by HPLC and enzyme kinetic parameters (Km and Vmax)
were calculated from the concentration data. The transformation of 4-dimethylaminoantipyrine to 4-
methyaminoantipyrine by microsomes prepared from baculovirus-expressed human CYP was pronounced
with CYP2D6. The metabolism of 4-dimethylaminoantipyrine was inhibited by 60.0% and 55.17% by a
concentration of 100 μmo per l of the known CYP2D6 inhibitors quinidine and moclobemide. The
corresponding Ki values were 0.050 and 0.11 mM, respectively. The corresponding IC50 values were 0.06
and 0.13 mM, respectively. The enzyme CYP2D6 apparently has an important role in N-demethyl-ation of
4-dimethylaminoantipyrine.
