Metabolism of Flumatinib, a Novel Antineoplastic Tyrosine Kinase Inhibitor, in Chronic Myelogenous Leukemia Patients
文献类型：期刊论文
| 作者 | Gong, Aishen1,2; Chen, Xiaoyan1 ; Deng, Pan1; Zhong, Dafang1
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2010-08 |
| 卷号 | 38期号:8页码:1328-1340 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.110.032326 |
| 文献子类 | Article |
| 英文摘要 | 4-(4-Methyl-piperazin-1-ylmethyl)-N-[6-methyl-5-(4-pyridin-3yl-pyrimidin-2-ylamino)-pyridin-3-yl]-3-trifluoromethyl-benzamide (flumatinib, HH-GV678), an antineoplastic tyrosine kinase inhibitor, is currently in Phase I clinical trials in China for the treatment of chronic myelogenous leukemia (CML). The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways of flumatinib in humans after oral administration. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 34 metabolites; 7 primary metabolites were confirmed by comparison with synthetic reference standards. The results show that the parent drug flumatinib was the main form recovered in human plasma, urine, and feces. The main metabolites of flumatinib in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis. In addition to these phase I metabolites, several phase II glucuronidation and acetylation products were detected in plasma, urine, and feces. The observed circulating metabolites included an N-demethylated metabolite (M1), two hydrolytic metabolites (M3, M4), oxidation metabolites (M2-1, M2-4, M2-7, M2-9, and M14), a glucuronide conjugate (M16-2), and several multiple metabolic products. Flumatinib was predominantly metabolized by amide bond cleavage to yield two corresponding hydrolytic products. By comparison with the related drug 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)-phenyl]-benzamide (imatinib), we concluded that the electron-withdrawing groups of trifluoromethyl and pyridine facilitated the amide bond cleavage and led to the in vivo formation of a carboxylic acid and an amine. |
| WOS关键词 | N-OXIDES ; IMATINIB ; REDUCTION ; AMINES |
| 资助项目 | NMR analysis[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000279956400009 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278811]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Zhong, Dafang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Shanghai Hengrui Pharmaceut Co Ltd, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Gong, Aishen,Chen, Xiaoyan,Deng, Pan,et al. Metabolism of Flumatinib, a Novel Antineoplastic Tyrosine Kinase Inhibitor, in Chronic Myelogenous Leukemia Patients[J]. DRUG METABOLISM AND DISPOSITION,2010,38(8):1328-1340. |
| APA | Gong, Aishen,Chen, Xiaoyan,Deng, Pan,&Zhong, Dafang.(2010).Metabolism of Flumatinib, a Novel Antineoplastic Tyrosine Kinase Inhibitor, in Chronic Myelogenous Leukemia Patients.DRUG METABOLISM AND DISPOSITION,38(8),1328-1340. |
| MLA | Gong, Aishen,et al."Metabolism of Flumatinib, a Novel Antineoplastic Tyrosine Kinase Inhibitor, in Chronic Myelogenous Leukemia Patients".DRUG METABOLISM AND DISPOSITION 38.8(2010):1328-1340. |
入库方式： OAI收割
来源：上海药物研究所
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