PT  - JOURNAL ARTICLE
AU  - Ring, B J
AU  - Catlow, J
AU  - Lindsay, T J
AU  - Gillespie, T
AU  - Roskos, L K
AU  - Cerimele, B J
AU  - Swanson, S P
AU  - Hamman, M A
AU  - Wrighton, S A
TI  - Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine.
DP  - 1996 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 658--666
VI  - 276
IP  - 2
4099  - http://jpet.aspetjournals.org/content/276/2/658.short
4100  - http://jpet.aspetjournals.org/content/276/2/658.full
SO  - J Pharmacol Exp Ther1996 Feb 01; 276
AB  - 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 observed 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 microliter/min/mg. NdM olanzapine formation by two human liver samples exhibited a CLint of 1.0 microliter/min/mg for the high affinity enzyme. The formation of N-O olanzapine was linear up to 300 microM olanzapine, yielding a CLint of 0.32 to 1.70 microliters/min/mg. The formation of 7-hydroxy olanzapine (7-OH olanzapine) exhibited an apparent Km of 24.2 microM. The rates of 2-OH olanzapine formation correlated with CYP2D6 levels and activity, and it was formed to the greatest extent by cDNA-expressed CYP2D6. N-O olanzapine formation correlated with human liver flavin-containing monooxygenase (FMO3) levels and activity. NdM olanzapine and 7-OH olanzapine formation correlated with CYP1A2 catalytic activities and they were formed to the greatest extent by expressed CYP1A2. These results suggest that CYP1A2 catalyzes NdM olanzapine and 7-OH olanzapine formation, CYP2D6 catalyzes 2-OH olanzapine formation and FMO3 catalyzes N-O olanzapine formation.