Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine.

摘要: The formation kinetics of 2-hydroxymethyl olanzapine (2-OH olanzapine), 4'-N-oxide (N-O olanzapine) and 4'-N-desmethyl (NdM were analyzed in vitro. Biphasic observed for 2-OH NdM olanzapine. high-affinity enzyme responsible by two human liver samples exhibited an intrinsic clearance (CLint) 0.2 microliter/min/mg. a CLint 1.0 microliter/min/mg the high affinity enzyme. N-O was linear up to 300 microM olanzapine, yielding 0.32 1.70 microliters/min/mg. 7-hydroxy (7-OH apparent Km 24.2 microM. rates correlated with CYP2D6 levels activity, it formed greatest extent cDNA-expressed CYP2D6. flavin-containing monooxygenase (FMO3) activity. 7-OH CYP1A2 catalytic activities they expressed CYP1A2. These results suggest that catalyzes formation, FMO3 formation.