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Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro.

Abstract

The antipsychotic drug quetiapine has been approved for the treatment of unipolar and bipolar depression. The antidepressant activity is considered to be mediated by the active metabolite N-desalkylquetiapine, which is mainly formed by CYP3A4. Little is known about the subsequent elimination of this metabolite. Therefore, this study investigated the possible involvement of cytochrome P450 (P450) enzymes in the metabolism of N-desalkylquetiapine. Screening for and interpretation of metabolites were performed by incubating N-desalkylquetiapine in human liver microsomes (HLM) followed by liquid chromatography-tandem mass spectrometry. The possible involvement of P450 enzymes in N-desalkylquetiapine metabolism was evaluated by coincubation of selective P450 inhibitors in HLM and subsequent experiments with recombinant human P450 enzymes. In HLM experiments, three chromatographic peaks were interpreted as possible metabolites of N-desalkylquetiapine, namely, N-desalkylquetiapine sulfoxide, 7-hydroxy-N-desalkylquetiapine, and an unrecognized metabolite (denoted M3). Inhibition of CYP2D6 (by quinidine) reduced formation of 7-hydroxy-N-desalkylquetiapine by 81%, whereas the CYP3A4 inhibitor ketoconazole inhibited formation of N-desalkylquetiapine sulfoxide and M3 by 65 and 34%, respectively. Inhibitors of CYP1A2, CYP2C9, and CYP2C19 showed only limited changes in metabolite formation. In recombinant systems, 7-hydroxy-N-desalkylquetiapine was exclusively formed by CYP2D6, whereas N-desalkylquetiapine sulfoxide and M3 were formed by both CYP3A4 and CYP2D6. Overall, intrinsic clearance of N-desalkylquetiapine was 12-fold higher by recombinant CYP2D6 relative to CYP3A4. In conclusion, N-desalkylquetiapine is metabolized by both CYP2D6 and CYP3A4 in vitro with preference for the former enzyme. The pharmacologically active metabolite, 7-hydroxy-N-desalkylquetiapine, was exclusively formed by CYP2D6, whereas the two other metabolites were mainly formed by CYP3A4.

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  • Authors+Show Affiliations

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    Center for Psychopharmacology, Diakonhjemmet Hospital, P.O. Box 85, Vinderen, N-0319 Oslo, Norway. gryvb@farmasi.uio.no

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    Source

    MeSH

    Antidepressive Agents
    Antipsychotic Agents
    Biotransformation
    Chromatography, Liquid
    Cytochrome P-450 CYP2D6
    Cytochrome P-450 CYP2D6 Inhibitors
    Cytochrome P-450 CYP3A
    Cytochrome P-450 CYP3A Inhibitors
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    Dealkylation
    Dibenzothiazepines
    Enzyme Inhibitors
    Humans
    Hydroxylation
    Kinetics
    Liver
    Microsomes, Liver
    Models, Biological
    Molecular Structure
    Quetiapine Fumarate
    Recombinant Proteins
    Substrate Specificity
    Sulfoxides
    Tandem Mass Spectrometry

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    22688609

    Citation

    Bakken, Gry Vibeke, et al. "Metabolism of the Active Metabolite of Quetiapine, N-desalkylquetiapine in Vitro." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 40, no. 9, 2012, pp. 1778-84.
    Bakken GV, Molden E, Knutsen K, et al. Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro. Drug Metab Dispos. 2012;40(9):1778-84.
    Bakken, G. V., Molden, E., Knutsen, K., Lunder, N., & Hermann, M. (2012). Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 40(9), pp. 1778-84. doi:10.1124/dmd.112.045237.
    Bakken GV, et al. Metabolism of the Active Metabolite of Quetiapine, N-desalkylquetiapine in Vitro. Drug Metab Dispos. 2012;40(9):1778-84. PubMed PMID: 22688609.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro. AU - Bakken,Gry Vibeke, AU - Molden,Espen, AU - Knutsen,Karoline, AU - Lunder,Niclas, AU - Hermann,Monica, Y1 - 2012/06/11/ PY - 2012/6/13/entrez PY - 2012/6/13/pubmed PY - 2013/1/18/medline SP - 1778 EP - 84 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 40 IS - 9 N2 - The antipsychotic drug quetiapine has been approved for the treatment of unipolar and bipolar depression. The antidepressant activity is considered to be mediated by the active metabolite N-desalkylquetiapine, which is mainly formed by CYP3A4. Little is known about the subsequent elimination of this metabolite. Therefore, this study investigated the possible involvement of cytochrome P450 (P450) enzymes in the metabolism of N-desalkylquetiapine. Screening for and interpretation of metabolites were performed by incubating N-desalkylquetiapine in human liver microsomes (HLM) followed by liquid chromatography-tandem mass spectrometry. The possible involvement of P450 enzymes in N-desalkylquetiapine metabolism was evaluated by coincubation of selective P450 inhibitors in HLM and subsequent experiments with recombinant human P450 enzymes. In HLM experiments, three chromatographic peaks were interpreted as possible metabolites of N-desalkylquetiapine, namely, N-desalkylquetiapine sulfoxide, 7-hydroxy-N-desalkylquetiapine, and an unrecognized metabolite (denoted M3). Inhibition of CYP2D6 (by quinidine) reduced formation of 7-hydroxy-N-desalkylquetiapine by 81%, whereas the CYP3A4 inhibitor ketoconazole inhibited formation of N-desalkylquetiapine sulfoxide and M3 by 65 and 34%, respectively. Inhibitors of CYP1A2, CYP2C9, and CYP2C19 showed only limited changes in metabolite formation. In recombinant systems, 7-hydroxy-N-desalkylquetiapine was exclusively formed by CYP2D6, whereas N-desalkylquetiapine sulfoxide and M3 were formed by both CYP3A4 and CYP2D6. Overall, intrinsic clearance of N-desalkylquetiapine was 12-fold higher by recombinant CYP2D6 relative to CYP3A4. In conclusion, N-desalkylquetiapine is metabolized by both CYP2D6 and CYP3A4 in vitro with preference for the former enzyme. The pharmacologically active metabolite, 7-hydroxy-N-desalkylquetiapine, was exclusively formed by CYP2D6, whereas the two other metabolites were mainly formed by CYP3A4. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/22688609/Metabolism_of_the_active_metabolite_of_quetiapine_N_desalkylquetiapine_in_vitro_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=22688609 DB - PRIME DP - Unbound Medicine ER -