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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.
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Citations
Cited by
Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation
Zanger, U. M., Turpeinen, M., Klein, K., & Schwab, M. (2008) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-008-2291-6 · Cited by 593
Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice
Gardiner, S. J., & Begg, E. J. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.3.6 · Cited by 406
Strawn, J. R., Geracioti, L., Rajdev, N., Clemenza, K., & Levine, A. (2018) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2018.1491966 · Cited by 214
Atypical Antipsychotics Part I: Pharmacology, Pharmacokinetics, and Efficacy
Markowitz, J. S., Brown, C. S., & Moore, T. R. (1999) · Annals of Pharmacotherapy · doi:10.1345/aph.17215 · Cited by 208
Relationship Between P-Glycoprotein and Second-Generation Antipsychotics
Moons, T., de Roo, M., Claes, S., & Dom, G. (2011) · Pharmacogenomics · doi:10.2217/pgs.11.55 · Cited by 122
Metadata
- Authors
- Ring, B. J., Catlow, J., Lindsay, T. J., Gillespie, T., Roskos, L. K., Cerimele, B. J., Swanson, S. P., Hamman, M. A., & Wrighton, S. A.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1996-02
- Volume
- 276
- Issue
- 2
- Pages
- 658-666
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1838133052
- Cited by
- 214
- References
- 0
- FWCI
- 10.97
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. https://app.cochat.ai/papers/10.1016/s0022-3565(25)12326-4
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- Ring, B. J., Catlow, J., Lindsay, T. J., Gillespie, T., Roskos, L. K., Cerimele, B. J., Swanson, S. P., Hamman, M. A., & Wrighton, S. A. (1996). Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. The Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1016/s0022-3565(25)12326-4
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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