Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients

doi:10.1111/bph.12047

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	Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients
	Xie, Cen2 ; Zhou, Jialan 2; Guo, Zitao 2; Diao, Xingxing 2; Gao, Zhiwei2 ; Zhong, Dafang2 ; Jiang, Haoyuan 1; Zhang, Lijia 1; Chen, Xiaoyan2
刊名	BRITISH JOURNAL OF PHARMACOLOGY
	2013-04
卷号	168 期号:7 页码:1687-1706
关键词	famitinib metabolism bioactivation quinone-imine hepatotoxicity
ISSN号	0007-1188
DOI	10.1111/bph.12047
文献子类	Article
英文摘要	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.
资助项目	National Natural Science Foundation of China[81173115] ; National Basic Research Program of China[2009CB930300]
WOS关键词	FULMINANT HEPATIC-FAILURE ; RENAL-CELL CARCINOMA ; IN-VITRO ; SUNITINIB ; LIVER ; LUNG ; HEPATOTOXICITY ; IDENTIFICATION ; ACETAMINOPHEN ; STRATEGIES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY-BLACKWELL
WOS记录号	WOS:000316262500013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277680]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	1.Jiangsu Hengrui Med Co Ltd, Liangyungang, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Xie, Cen,Zhou, Jialan,Guo, Zitao,et al. Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients[J]. BRITISH JOURNAL OF PHARMACOLOGY,2013,168(7):1687-1706.
APA	Xie, Cen.,Zhou, Jialan.,Guo, Zitao.,Diao, Xingxing.,Gao, Zhiwei.,...&Chen, Xiaoyan.(2013).Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients.BRITISH JOURNAL OF PHARMACOLOGY,168(7),1687-1706.
MLA	Xie, Cen,et al."Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients".BRITISH JOURNAL OF PHARMACOLOGY 168.7(2013):1687-1706.