IDENTIFICATION OF THE HUMAN CYTOCHROMES P450 RESPONSIBLE FOR THE IN-VITRO FORMATION OF THE MAJOR OXIDATIVE METABOLITES OF THE ANTIPSYCHOTICAGENT OLANZAPINE

The formation kinetics of 2-hydroxymethyl olanzapine (2-OH olanzapine) , 4'-N-oxide olanzapine (N-O olanzapine) and 4'-N-desmethyl olanzapine (NdM olanzapine) were analyzed in vitro. Biphasic kinetics were obser ved for formation of 2-OH and NdM olanzapine. The high-affinity enzyme responsible for 2-OH olanzapine formation by two human liver samples exhibited an intrinsic clearance (CLint) of 0.2 mu l/min/mg. NdM olanz apine formation by two human liver samples exhibited a CLint of 1.0 mu l/min/mg for the high affinity enzyme. The formation of N-O olanzapin e was linear up to 300 mu M olanzapine, yielding a CLint of 0.32 to 1. 70 mu l/min/mg. The formation of 7-hydroxy olanzapine (7-OH olanzapine ) exhibited an apparent K-m of 24.2 mu M. The rates of 2-OH olanzapine formation correlated with CYP2D6 levels and activity, and it was form ed to the greatest extent by cDNA-expressed CYP2D6. N-O olanzapine for mation correlated with human liver flavin-containing monooxygenase (FM O3) levels and activity. NdM olanzapine and 7-OH olanzapine formation correlated with CYP1A2 catalytic activities and they were formed to th e greatest extent by expressed CYP1A2. These results suggest that CYP1 A2 catalyzes NdM olanzapine and 7-OH olanzapine formation, CYP2D6 cata lyzes 2-OH olanzapine formation and FMO3 catalyzes N-O olanzapine form ation.