Gabel Florian, Aubry Anne-Sophie, Hovhannisyan Volodya, Chavant Virginie, Weinsanto Ivan, Maduna Tando, Darbon Pascal, Goumon Yannick
CNRS UPR3212, Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, University of Strasbourg, Strasbourg, France.
Mass Spectrometry Facilities of the CNRS UPR3212, Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
Front Oncol. 2020 Feb 21;10:25. doi: 10.3389/fonc.2020.00025. eCollection 2020.
Tamoxifen is used to treat breast cancer and cancer recurrences. After administration, tamoxifen is converted into two more potent antitumor compounds, 4OH-tamoxifen and endoxifen by the CYP3A4/5 and 2D6 enzymes in human. These active compounds are inactivated by the same UDP-glucuronosyltransferase isoforms as those involved in the metabolism of morphine. Importantly, cancer-associated pain can be treated with morphine, and the common metabolic pathway of morphine and tamoxifen suggests potential clinically relevant interactions. Mouse liver microsomes were used to determine the impact of morphine on 4OH-tamoxifen metabolism . For experiments, female mice were first injected with tamoxifen alone and then with tamoxifen and morphine. Blood was collected, and LC-MS/MS was used to quantify tamoxifen, 4OH-tamoxifen, N-desmethyltamoxifen, endoxifen, 4OH-tamoxifen-glucuronide, and endoxifen-glucuronide. , we found increased values for the production of 4OH-tamoxifen-glucuronide in the presence of morphine, suggesting an inhibitory effect on 4OH-tamoxifen glucuronidation. Conversely, morphine treatment decreased 4OH-tamoxifen levels in the blood while dramatically increasing the formation of inactive metabolites 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Our findings emphasize the need for caution when extrapolating results from metabolic assays to drug metabolism interactions. Importantly, morphine strongly impacts tamoxifen metabolism in mice. It suggests that tamoxifen efficiency could be reduced when both drugs are co-administered in a clinical setting, e.g., to relieve pain in breast cancer patients. Further studies are needed to assess the potential for tamoxifen-morphine metabolic interactions in humans.
他莫昔芬用于治疗乳腺癌及癌症复发。给药后，他莫昔芬在人体内被细胞色素P450 3A4/5和2D6酶转化为两种活性更强的抗肿瘤化合物，即4-羟基他莫昔芬和内昔芬。这些活性化合物通过与参与吗啡代谢相同的尿苷二磷酸葡萄糖醛酸基转移酶亚型失活。重要的是，癌症相关疼痛可用吗啡治疗，且吗啡和他莫昔芬的共同代谢途径提示了潜在的临床相关相互作用。使用小鼠肝微粒体来确定吗啡对4-羟基他莫昔芬代谢的影响。在实验中，首先给雌性小鼠单独注射他莫昔芬，然后注射他莫昔芬和吗啡。采集血液，并用液相色谱-串联质谱法对他莫昔芬、4-羟基他莫昔芬、N-去甲基他莫昔芬、内昔芬、4-羟基他莫昔芬葡萄糖醛酸苷和内昔芬葡萄糖醛酸苷进行定量。我们发现，在吗啡存在的情况下，4-羟基他莫昔芬葡萄糖醛酸苷生成的数值增加，表明对4-羟基他莫昔芬葡萄糖醛酸化有抑制作用。相反，吗啡处理降低了血液中4-羟基他莫昔芬的水平，同时显著增加了无活性代谢物4-羟基他莫昔芬葡萄糖醛酸苷和内昔芬葡萄糖醛酸苷的形成。我们的研究结果强调，在将代谢试验结果外推至药物代谢相互作用时需谨慎。重要的是，吗啡对小鼠体内他莫昔芬的代谢有强烈影响。这表明，在临床环境中同时使用这两种药物（例如用于缓解乳腺癌患者的疼痛）时，他莫昔芬的疗效可能会降低。需要进一步研究来评估他莫昔芬与吗啡在人体中的代谢相互作用潜力。
