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Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species

文献类型：期刊论文

作者Zhong, Chen-chun1,2; Chen, Feng1; Yang, Jun-ling1; Jia, Wei-wei1; Li, Li1; Cheng, Chen1; Du, Fei-fei1; Zhang, Su-ping1; Xie, Cheng-ying1; Zhang, Na-ting1
刊名ACTA PHARMACOLOGICA SINICA
出版日期2018-06
卷号39期号:6页码:1048-1063
关键词anlotinib tyrosine kinase inhibitor absorption distribution metabolism excretion pharmacokinetics
ISSN号1671-4083
DOI10.1038/aps.2017.199
文献子类Article
英文摘要Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22.8 +/- 11.0 h) was longer than that in rats (5.1 +/- 1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35 +/- 1.31 L.h(-1).kg(-1); dogs, 0.40 +/- 0.06 L.h(-1).kg(-1)). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6 +/- 3.1 L/kg) and dogs (6.6 +/- 2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to alpha(1)-acid glycoprotein or gamma-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 mu mol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding.
WOS关键词HUMAN UDP-GLUCURONOSYLTRANSFERASES ; HERB-DRUG INTERACTIONS ; ALPHA(1)-ACID GLYCOPROTEIN ; MOLECULAR-MECHANISMS ; SYSTEMIC EXPOSURE ; CANCER-THERAPY ; IN-VITRO ; METABOLISM ; RESISTANCE ; HEPATOTOXICITY
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:6264828
WOS记录号WOS:000434380400015
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/279727]  
专题上海药物代谢研究中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
科研与新药推进处
通讯作者Niu, Wei; Li, Chuan
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
2.Univ Chinese Acad Sci, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhong, Chen-chun,Chen, Feng,Yang, Jun-ling,et al. Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species[J]. ACTA PHARMACOLOGICA SINICA,2018,39(6):1048-1063.
APA Zhong, Chen-chun.,Chen, Feng.,Yang, Jun-ling.,Jia, Wei-wei.,Li, Li.,...&Li, Chuan.(2018).Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species.ACTA PHARMACOLOGICA SINICA,39(6),1048-1063.
MLA Zhong, Chen-chun,et al."Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species".ACTA PHARMACOLOGICA SINICA 39.6(2018):1048-1063.

入库方式： OAI收割

来源：上海药物研究所

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