Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients
Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients
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新型受体酪氨酸激酶抑制剂法米替尼在癌症患者中的代谢和生物活性
DOI：
10.1111/bph.12047
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发表时间：
2013-04-01
影响因子：
7.3
通讯作者：
Chen, Xiaoyan
中科院分区：
文献类型：
--
作者：
Xie, Cen;Zhou, Jialan;Chen, Xiaoyan
背景与目的Famitinib是一种新型的多靶点酪氨酸激酶受体抑制剂，正在开发用于癌症治疗。本研究旨在表征法米替尼的代谢和生物活化途径。实验方法采用超高效液相色谱-四极杆飞行时间质谱法对人体血浆、尿液和粪便中的代谢物进行鉴定，并用合成标准品进行鉴定。利用微粒体、重组代谢酶和肝细胞研究生物转化和生物激活机制。经多次口服后，Famitinib被广泛代谢。未改变的福米替尼是主要的循环物质，其次是n -去乙基福米替尼（M3），其稳态暴露量为母体药物的7.2 ~ 7.5%。排泄物中的代谢物主要来自氧化脱胺（M1）、n -去乙基化（M3）、氧化脱氟（M7）、吲哚吡啶羟基化（M9-1和M9-5）和次级ii相偶联。CYP3A4/5对M3的形成起主要作用，CYP3A4/5和醛脱氢酶对M1的形成起主要作用，CYP1A1/2对M7、M9-1和M9-5的形成起主要作用。在血浆、尿液和粪便中观察到少量半胱氨酸偶联物，这意味着形成了活性中间体。体外微粒体研究证明，famitinib通过CYP1A1/2在吲哚吡啶上的环氧化和自发的去氟重排产生醌-亚胺物种而被生物激活。在人原代肝细胞中观察到法米替尼肝毒性与其生物活性之间的相关性。结论和意义法米替尼在癌症患者体内具有良好的吸收和广泛的代谢。多种酶，主要是CYP3A4/5和CYP1A1/2参与法米替尼代谢清除。通过生物活化形成的醌-亚胺中间体可能与法米替尼肝毒性有关。共同施用CYP1A1/2诱导剂或抑制剂可增强或抑制其肝毒性。
Background and Purpose Famitinib is a novel multi-targeted receptor tyrosine kinase inhibitor under development for cancer treatment. This study aims to characterize the metabolic and bioactivation pathways of famitinib. Experimental Approach The metabolites in human plasma, urine and feces were identified via ultra-high performance liquid chromatography-quadrupole-time of flight-mass spectrometry and confirmed using synthetic standards. Biotransformation and bioactivation mechanisms were investigated using microsomes, recombinant metabolic enzymes and hepatocytes. Key Results Famitinib was extensively metabolized after repeated oral administrations. Unchanged famitinib was the major circulating material, followed by N-desethylfaminitib (M3), whose steady-state exposure represented 7.2 to 7.5% that of the parent drug. Metabolites in the excreta were mainly from oxidative deamination (M1), N-desethylation (M3), oxidative defluorination (M7), indolylidene hydroxylation (M9-1 and M9-5) and secondary phase-II conjugations. CYP3A4/5 was the major contributor to M3 formation, CYP3A4/5 and aldehyde dehydrogenase to M1 formation and CYP1A1/2 to M7, M9-1 and M9-5 formations. Minor cysteine conjugates were observed in the plasma, urine and feces, implying the formation of reactive intermediate(s). In vitro microsomal studies proved that famitinib was bioactivated through epoxidation at indolylidene by CYP1A1/2 and spontaneously defluorinated rearrangement to afford a quinone-imine species. A correlation between famitinib hepatotoxicity and its bioactivation was observed in the primary human hepatocytes. Conclusion and Implications Famitinib is well absorbed and extensively metabolized in cancer patients. Multiple enzymes, mainly CYP3A4/5 and CYP1A1/2, are involved in famitinib metabolic clearance. The quinone-imine intermediate formed through bioactivation may be associated with famitinib hepatotoxicity. Co-administered CYP1A1/2 inducers or inhibitors may potentiate or suppress its hepatotoxicity.