Application of Mice Humanized for CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants.
Application of Mice Humanized for CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants.
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DOI：
10.1124/dmd.116.073437
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Wolf CR
中科院分区：
文献类型：
--
作者：
MacLeod AK;McLaughlin LA;Henderson CJ;Wolf CR
他莫昔芬是一种雌激素受体拮抗剂，用于治疗乳腺癌。它是一种前药，可被多种细胞色素 P450 酶转化为主要代谢物 N-去甲基他莫昔芬 (NDT)，然后被 CYP2D6 进一步修饰为药理学有效的次级代谢物 4-羟基-N-去甲基他莫昔芬（endoxifen）。接受他莫昔芬治疗的患者通常会同时服用抗抑郁药 (AD)，它们也由 CYP2D6 代谢，有证据表明这些药物之间的药物相互作用会抑制内多昔芬的形成，从而对他莫昔芬治疗的结果产生不利影响。我们在 CYP2D6 人源化小鼠 (hCYP2D6) 体内评估了这种潜在重要的药物相互作用。 hCYP2D6 小鼠肝微粒体 (MLM) 在体外将 NDT 转化为艾多昔芬的速率与 13 个人类肝微粒体组中最活跃的成员相似。与 CYP2D6 抑制剂奎尼丁共孵育可消除 hCYP2D6 MLM 产生的内多昔芬。野生型MLM的NDT羟基化活性比hCYP2D6高7.4倍，而来自Cyp2d敲除动物的MLM则无活性。在人肝微粒体组中，NDT 的羟基化与布呋洛尔（一种 CYP2D6 探针底物）的羟基化相关。在体外，选择性血清素再摄取抑制剂类 AD 是 hCYP2D6 MLM 的 NDT 羟基化抑制剂，比三环类化合物更有效一个数量级。在临床相关剂量下，帕罗西汀预处理可抑制 hCYP2D6 小鼠体内 NDT 产生内多昔芬。这些数据表明 AD 有可能影响内多昔芬的生成，从而影响他莫昔芬治疗的结果。
Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome 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). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug–drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. We evaluated this potentially important drug–drug interaction in vivo in mice humanized for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLMs) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes. Coincubation with quinidine, a CYP2D6 inhibitor, ablated endoxifen generation by hCYP2D6 MLMs. The NDT-hydroxylation activity of wild-type MLMs was 7.4 times higher than that of hCYP2D6, whereas MLMs from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the human liver microsome panel. In vitro, ADs of the selective serotonin reuptake inhibitor class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLMs than were compounds of the tricyclic class. At a clinically relevant dose, paroxetine pretreatment 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.
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影响因子：
5.5
作者：
Cascorbi, I
通讯作者：
Cascorbi, I
影响因子：
3.9
作者：
Bertelsen, KM;Venkatakrishnan, K;Greenblatt, DJ
通讯作者：
Greenblatt, DJ
影响因子：
10.3
作者：
Jin, Y;Desta, Z;Flockhart, DA
通讯作者：
Flockhart, DA
影响因子：
3.9
作者：
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通讯作者：
Ly, Justin
DOI：
10.1097/01213011-199912000-00004
发表时间：
1999-12-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Dalén, P;Dahl, ML;Wilkinson, GR
通讯作者：
Wilkinson, GR