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

doi:10.1038/aps.2017.199

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	Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species
	Zhong, Chen-chun 1,2; Chen, Feng 1; Yang, Jun-ling1 ; Jia, Wei-wei 1; Li, Li 1; Cheng, Chen 1; Du, Fei-fei 1; Zhang, Su-ping 1; Xie, Cheng-ying1 ; Zhang, Na-ting 1
刊名	ACTA PHARMACOLOGICA SINICA
	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
DOI	10.1038/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
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000434380400015
内容类型	期刊论文
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.