Application of Mice Humanised for Cytochrome P450 CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants

A. Kenneth MacLeod, Lesley A. McLaughlin, Colin J. Henderson, C. Roland Wolf (Lead / Corresponding author)

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    Abstract

    Tamoxifen is an oestrogen-receptor (ER) antagonist used in the treatment of breast cancer. It is a prodrug, converted by several P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Anti-depressants (ADs), which are often co-prescribed to patients receiving tamoxifen, are also metabolised by CYP2D6 and evidence suggests that a drugdrug interaction (DDI) between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. Here, we have evaluated this potentially important DDI in vivo, in mice humanised for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLM) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes (HLM). Co-incubation with the CYP2D6 inhibitor, quinidine, ablated endoxifen generation by hCYP2D6 MLM. The NDT-hydroxylation activity of wild-type MLM was 7.4 times higher than that of hCYP2D6, while MLM from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the HLM panel. In vitro, ADs of the selective serotonin reuptake inhibitor (SSRI) class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLM than were compounds of the tricyclic class. At a clinically-relevant dose, paroxetine pre-treatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy.
    Original languageEnglish
    Pages (from-to)17-22
    Number of pages6
    JournalDrug Metabolism and Disposition
    Volume45
    Issue number1
    Early online date18 Oct 2016
    DOIs
    Publication statusPublished - Jan 2017

    Fingerprint

    Cytochrome P-450 CYP2D6
    Tamoxifen
    Drug Interactions
    Cytochrome P-450 Enzyme System
    Antidepressive Agents
    Liver Microsomes
    Pharmaceutical Preparations
    Hydroxylation
    Paroxetine
    Quinidine
    Prodrugs
    Serotonin Uptake Inhibitors
    Therapeutics
    4-hydroxy-N-desmethyltamoxifen
    N-desmethyltamoxifen
    Breast Neoplasms

    Keywords

    • animal models
    • anticancer agents
    • bioativation
    • cytochrome P450
    • drug-drug interactions
    • genetically modified animal models
    • metabolite disposition
    • NADPH cytopchrome P450 reductase
    • pharmacokinetics
    • prodrugs

    Cite this

    @article{267b7ec4273d48b089e13abbfd105e93,
    title = "Application of Mice Humanised for Cytochrome P450 CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants",
    abstract = "Tamoxifen is an oestrogen-receptor (ER) antagonist used in the treatment of breast cancer. It is a prodrug, converted by several P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Anti-depressants (ADs), which are often co-prescribed to patients receiving tamoxifen, are also metabolised by CYP2D6 and evidence suggests that a drugdrug interaction (DDI) between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. Here, we have evaluated this potentially important DDI in vivo, in mice humanised for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLM) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes (HLM). Co-incubation with the CYP2D6 inhibitor, quinidine, ablated endoxifen generation by hCYP2D6 MLM. The NDT-hydroxylation activity of wild-type MLM was 7.4 times higher than that of hCYP2D6, while MLM from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the HLM panel. In vitro, ADs of the selective serotonin reuptake inhibitor (SSRI) class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLM than were compounds of the tricyclic class. At a clinically-relevant dose, paroxetine pre-treatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy.",
    keywords = "animal models, anticancer agents, bioativation, cytochrome P450, drug-drug interactions, genetically modified animal models, metabolite disposition, NADPH cytopchrome P450 reductase, pharmacokinetics, prodrugs",
    author = "MacLeod, {A. Kenneth} and McLaughlin, {Lesley A.} and Henderson, {Colin J.} and Wolf, {C. Roland}",
    note = "This work was supported by Cancer Research UK [C4639/A10822].",
    year = "2017",
    month = "1",
    doi = "10.1124/dmd.116.073437",
    language = "English",
    volume = "45",
    pages = "17--22",
    journal = "Drug Metabolism and Disposition",
    issn = "0090-9556",
    publisher = "American Society for Pharmacology and Experimental Therapeutics",
    number = "1",

    }

    TY - JOUR

    T1 - Application of Mice Humanised for Cytochrome P450 CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants

    AU - MacLeod, A. Kenneth

    AU - McLaughlin, Lesley A.

    AU - Henderson, Colin J.

    AU - Wolf, C. Roland

    N1 - This work was supported by Cancer Research UK [C4639/A10822].

    PY - 2017/1

    Y1 - 2017/1

    N2 - Tamoxifen is an oestrogen-receptor (ER) antagonist used in the treatment of breast cancer. It is a prodrug, converted by several P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Anti-depressants (ADs), which are often co-prescribed to patients receiving tamoxifen, are also metabolised by CYP2D6 and evidence suggests that a drugdrug interaction (DDI) between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. Here, we have evaluated this potentially important DDI in vivo, in mice humanised for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLM) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes (HLM). Co-incubation with the CYP2D6 inhibitor, quinidine, ablated endoxifen generation by hCYP2D6 MLM. The NDT-hydroxylation activity of wild-type MLM was 7.4 times higher than that of hCYP2D6, while MLM from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the HLM panel. In vitro, ADs of the selective serotonin reuptake inhibitor (SSRI) class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLM than were compounds of the tricyclic class. At a clinically-relevant dose, paroxetine pre-treatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy.

    AB - Tamoxifen is an oestrogen-receptor (ER) antagonist used in the treatment of breast cancer. It is a prodrug, converted by several P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Anti-depressants (ADs), which are often co-prescribed to patients receiving tamoxifen, are also metabolised by CYP2D6 and evidence suggests that a drugdrug interaction (DDI) between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. Here, we have evaluated this potentially important DDI in vivo, in mice humanised for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLM) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes (HLM). Co-incubation with the CYP2D6 inhibitor, quinidine, ablated endoxifen generation by hCYP2D6 MLM. The NDT-hydroxylation activity of wild-type MLM was 7.4 times higher than that of hCYP2D6, while MLM from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the HLM panel. In vitro, ADs of the selective serotonin reuptake inhibitor (SSRI) class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLM than were compounds of the tricyclic class. At a clinically-relevant dose, paroxetine pre-treatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy.

    KW - animal models

    KW - anticancer agents

    KW - bioativation

    KW - cytochrome P450

    KW - drug-drug interactions

    KW - genetically modified animal models

    KW - metabolite disposition

    KW - NADPH cytopchrome P450 reductase

    KW - pharmacokinetics

    KW - prodrugs

    U2 - 10.1124/dmd.116.073437

    DO - 10.1124/dmd.116.073437

    M3 - Article

    C2 - 27756789

    VL - 45

    SP - 17

    EP - 22

    JO - Drug Metabolism and Disposition

    JF - Drug Metabolism and Disposition

    SN - 0090-9556

    IS - 1

    ER -