Metabolism and Pharmacokinetics of Allitinib in Cancer Patients: The Roles of Cytochrome P450s and Epoxide Hydrolase in its Biotransformation
文献类型：期刊论文
| 作者 | Lin, Lishan; Xie, Cen ; Gao, Zhiwei; Chen, Xiaoyan; Zhong, Dafang
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2014-05 |
| 卷号 | 42期号:5页码:872-884 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.113.056341 |
| 文献子类 | Article |
| 英文摘要 | Allitinib, a novel irreversible selective inhibitor of the epidermal growth factor receptor (EGFR) 1 and human epidermal receptor 2 (ErbB2), is currently in clinical trials in China for the treatment of solid tumors. It is a structural analog of lapatinib but has an acrylamide side chain. Sixteen metabolites of allitinib were detected by ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. The pharmacologically active alpha,beta-unsaturated carbonyl group was the major metabolic site. The metabolic pathways included O-dealkylation, amide hydrolysis, dihydrodiol formation, hydroxylation, and secondary phase 2 conjugation. The metabolite of amide hydrolysis (M6) and 27,28-dihydrodiol allitinib (M10) were the major pharmacologically active metabolites in the circulation. The steady-state exposures to M6 and M10 were 11% and 70% of that of allitinib, respectively. The biotransformation of allitinib was determined using microsomes and recombinant metabolic enzymes. In vitro phenotyping studies demonstrated that multiple cytochrome P450 (P450) isoforms, mainly CYP3A4/5 and CYP1A2, were involved in the metabolism of allitinib. Thiol conjugates (M14 and M16) and dihydrodiol metabolites (M5 and M10) were detected in humans, implying the formation of reactive intermediates. The formation of a glutathione conjugate of allitinib was independent of NADPH and P450 isoforms, but was catalyzed by glutathione-S-transferase. P450 enzymes and epoxide hydrolase were involved in M10 formation. Overall, our study showed that allitinib was metabolized by the O-dealkylation pathway similar to lapatinib, but that amide hydrolysis and the formation of dihydrodiol were the dominant metabolic pathways. The absorbed allitinib was extensively metabolized by multiple enzymes. |
| WOS关键词 | GROWTH-FACTOR RECEPTOR ; ADVANCED SOLID TUMORS ; KINASE INHIBITOR ; TYROSINE KINASE ; ANTITUMOR-ACTIVITY ; SIGNALING NETWORK ; PROPYLENE-OXIDE ; DUAL INHIBITOR ; LAPATINIB ; MICROSOMES |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| WOS记录号 | WOS:000334360200010 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277107]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Zhong, Dafang |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lin, Lishan,Xie, Cen,Gao, Zhiwei,et al. Metabolism and Pharmacokinetics of Allitinib in Cancer Patients: The Roles of Cytochrome P450s and Epoxide Hydrolase in its Biotransformation[J]. DRUG METABOLISM AND DISPOSITION,2014,42(5):872-884. |
| APA | Lin, Lishan,Xie, Cen,Gao, Zhiwei,Chen, Xiaoyan,&Zhong, Dafang.(2014).Metabolism and Pharmacokinetics of Allitinib in Cancer Patients: The Roles of Cytochrome P450s and Epoxide Hydrolase in its Biotransformation.DRUG METABOLISM AND DISPOSITION,42(5),872-884. |
| MLA | Lin, Lishan,et al."Metabolism and Pharmacokinetics of Allitinib in Cancer Patients: The Roles of Cytochrome P450s and Epoxide Hydrolase in its Biotransformation".DRUG METABOLISM AND DISPOSITION 42.5(2014):872-884. |
入库方式： OAI收割
来源：上海药物研究所
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