CYP2D6 gene polymorphism and apatinib affect the metabolic profile of fluvoxamine.
CYP2D6 gene polymorphism and apatinib affect the metabolic profile of fluvoxamine.
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DOI：
10.3389/fphar.2022.985159
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
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本研究旨在1）研究CYP2D6变异对氟伏沙明催化的影响，2）研究氟伏沙明和阿帕替尼之间的相互作用。建立了酶反应体系并测定了CYP2D6代谢氟伏沙明的动力学曲线。在体内，使用 Sprague-Dawley (SD) 大鼠研究了药物间相互作用。氟伏沙明在联合或不联合阿帕替尼的情况下进行管饲。采用超高效液相色谱-串联质谱法(UPLC-MS/MS)测定氟伏沙明和去甲基氟伏沙明的浓度。结果表明，CYP2D6.A5V、V104A、D337G、F164L、V342M、R440C和R497C的相对清除率与CYP2D6.1相比显着增加，范围从153.626%±6.718%到394.310%±33.268%。其他变异体活性均有不同程度降低，甚至丧失功能，但无统计学差异。测定了阿帕替尼针对氟伏沙明处置的 IC50，在 RLM 中和 HLM 中分别为 0.190 μM 和 6.419 μM。在体内，阿帕替尼可以增强氟伏沙明的血浆暴露，其显着特征是增加 AUC、Tmax 和 Cmax。同时，去甲基氟伏沙明的产生受到显着抑制，AUC和Cmax均显着下降。从机制上讲，阿帕替尼在 RLM 和 HLM 中以混合方式抑制氟伏沙明代谢物的产生。此外，阿帕替尼抑制CYP2D6.1、2和10之间氟伏沙明代谢的效力存在差异。综上所述，CYP2D6基因多态性和药物间相互作用可显着影响氟伏沙明的血浆暴露。本研究为指导氟伏沙明个体化应用提供基础数据。
This study aimed 1) to investigate the influence of CYP2D6 variants on the catalyzing of fluvoxamine, and 2) to study the interaction between fluvoxamine and apatinib. An enzymatic reaction system was setup and the kinetic profile of CYP2D6 in metabolizing fluvoxamine was determined. In vivo, drug-drug interaction was investigated using Sprague–Dawley (SD) rats. Fluvoxamine was given gavage with or without apatinib. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the concentrations of fluvoxamine and desmethyl-fluvoxamine. The results demonstrated that the relative clearance rates of CYP2D6.A5V, V104A, D337G, F164L, V342M, R440C and R497C increased significantly compared with CYP2D6.1, ranging from 153.626% ± 6.718% to 394.310% ± 33.268%. The activities of other variants reduced to different extent, or even lost function, but there was no statistical difference. The IC50 of apatinib against fluvoxamine disposition was determined, which is 0.190 μM in RLM and 6.419 μM in HLM, respectively. In vivo, apatinib can enhance the plasma exposure of fluvoxamine remarkably characterized by increased AUC, Tmax and Cmax. Meanwhile, the produce of desmethyl fluvoxamine was dramatically inhibited, both AUC and Cmax decreased significantly. Mechanistically, apatinib inhibit the generation of fluvoxamine metabolite with a mixed manner both in RLM and HLM. Furthermore, there were differences in the potency of apatinib in suppressing fluvoxamine metabolism among CYP2D6.1, 2 and 10. In conclusion, CYP2D6 gene polymorphisms and drug-drug interaction can remarkably affect the plasma exposure of fluvoxamine. The present study provides basis data for guiding individual application of fluvoxamine.
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