title: Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine.
abstract: 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.
authors.affiliation: Department of Drug Metabolism and Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Ring
authors.forename: J
authors.initials: J
authors.lastname: Catlow
authors.forename: T J
authors.initials: TJ
authors.lastname: Lindsay
authors.forename: T
authors.initials: T
authors.lastname: Gillespie
authors.forename: L K
authors.initials: LK
authors.lastname: Roskos
authors.forename: B J
authors.initials: BJ
authors.lastname: Cerimele
authors.forename: S P
authors.initials: SP
authors.lastname: Swanson
authors.forename: M A
authors.initials: MA
authors.lastname: Hamman
authors.forename: S A
authors.initials: SA
authors.lastname: Wrighton
mesh_terms: D014150:Antipsychotic Agents / Q000378:metabolism*; D001569:Benzodiazepines; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000502:physiology; D000077152:Olanzapine; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000502:physiology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D010890:Pirenzepine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D000077152:Olanzapine