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Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans

文献类型：期刊论文

作者Ding, Juefang2; Chen, Xiaoyan2; Gao, Zhiwei2; Dai, Xiaojian2; Li, Liang2; Xie, Cen2; Jiang, Haoyuan1; Zhang, Lijia1; Zhong, Dafang2
刊名DRUG METABOLISM AND DISPOSITION
出版日期2013-06
卷号41期号:6页码:1195-1210
ISSN号0090-9556
DOI10.1124/dmd.112.050310
文献子类Article
英文摘要Apatinib is a new oral antiangiogenic molecule that inhibits vascular endothelial growth factor receptor-2. The present study aimed to determine the metabolism, pharmacokinetics, and excretion of apatinib in humans and to identify the enzymes responsible for its metabolism. The primary routes of apatinib biotransformation included E-and Z-cyclopentyl-3-hydroxylation, N-dealkylation, pyridyl-25-N- oxidation, 16-hydroxylation, dioxygenation, and O-glucuronidation after 3-hydroxylation. Nine major metabolites were confirmed by comparison with reference standards. The total recovery of the administered dose was 76.8% within 96 hours postdose, with 69.8 and 7.02% of the administered dose excreted in feces and urine, respectively. About 59.0% of the administered dose was excreted unchanged via feces. Unchanged apatinib was detected in negligible quantities in urine, indicating that systemically available apatinib was extensively metabolized. The major circulating metabolite was the pharmacologically inactive E-3-hydroxy-apatinib-O- glucuronide (M9-2), the steady-state exposure of which was 125% that of the apatinib. The steady-state exposures of E-3-hydroxy- apatinib (M1-1), Z-3-hydroxy-apatinib (M1-2), and apatinib-25- N-oxide (M1-6) were 56, 22, and 32% of parent drug exposure, respectively. Calculated as pharmacological activity index values, the contribution of M1-1 to the pharmacology of the drug was 5.42 to 19.3% that of the parent drug. The contribution of M1-2 and M1-6 to the pharmacology of the drug was less than 1%. Therefore, apatinib was a major contributor to the overall pharmacological activity in humans. Apatinib was metabolized primarily by CYP3A4/ 5 and, to a lesser extent, by CYP2D6, CYP2C9, and CYP2E1. UGT2B7 was the main enzyme responsible for M9-2 formation. Both UGT1A4 and UGT2B7 were responsible for Z-3-hydroxyapatinib- O-glucuronide (M9-1) formation.
WOS关键词UDP-GLUCURONOSYLTRANSFERASE 2B7 ; HUMAN LIVER ; TYROSINE KINASE ; IN-VITRO ; N-OXIDES ; YN968D1 ; ANGIOGENESIS ; CANCER ; GLUCURONIDATION ; HYPERTENSION
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000318971400005
出版者AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
源URL[http://119.78.100.183/handle/2S10ELR8/277605]  
专题上海药物代谢研究中心
通讯作者Zhong, Dafang
作者单位1.Jiangsu Hengrui Med Co Ltd, Lianyungang, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Ding, Juefang,Chen, Xiaoyan,Gao, Zhiwei,et al. Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans[J]. DRUG METABOLISM AND DISPOSITION,2013,41(6):1195-1210.
APA Ding, Juefang.,Chen, Xiaoyan.,Gao, Zhiwei.,Dai, Xiaojian.,Li, Liang.,...&Zhong, Dafang.(2013).Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans.DRUG METABOLISM AND DISPOSITION,41(6),1195-1210.
MLA Ding, Juefang,et al."Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans".DRUG METABOLISM AND DISPOSITION 41.6(2013):1195-1210.

入库方式： OAI收割

来源：上海药物研究所

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