Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study

doi:10.1016/j.jpha.2018.09.001

	Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study
	Jia, Weiwei 1; Li, Jing 1,2; Du, Feifei 1; Sun, Yan 3; Xu, Fang 1; Wang, Fengqing 1; Olaleye, Olajide E.1; Chen, Danghui 1,4; Tang, Wei 1; Zuo, Jianping 1
刊名	JOURNAL OF PHARMACEUTICAL ANALYSIS
	2019-02-01
卷号	9 期号:1 页码:25-33
关键词	S-adenosyl-L-homocysteine hydrolase DZ2002 Carboxylesterases Pharmacokinetics
ISSN号	2095-1779
DOI	10.1016/j.jpha.2018.09.001
通讯作者	Li, Chuan(chli@simm.ac.cn)
英文摘要	Methyl (S)-4-(6-amino-9H-purin-9-yl)-2-hydroxybutanoate (DZ2002) is a potent reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH). Due to its ester structure, DZ2002 is rapidly hydrolyzed in rat blood to 4-(6-amino-9H-purin-9-yl)-2-hydroxybutyric acid (DZA) during and after blood sampling from rats; this hampers accurate determination of the circulating DZ2002 and its acid metabolite DZA in rats. To this end, a method for determining the blood concentrations of DZ2002 and DZA in rats was developed by using methanol to immediately deactivate blood carboxylesterases during sampling. The newly developed bioanalytical assay possessed favorable accuracy and precision with lower limit of quantification of 31 nM for DZ2002 and DZA. This validated assay was applied to a rat pharmacokinetic study of DZ2002. After oral administration, DZ2002 was found to be extensively converted into DZA. The level of systemic exposure to DZ2002 was significantly lower than that of DZA. The apparent oral bioavailability of DZ2002 was 90%-159%. The mean terminal half-lives of DZ2002 and DZA were 0.3-0.9 and 1.3-5.1 h, respectively. The sample preparation method illustrated here may be adopted for determination of other circulating ester drugs and their acid metabolites in rodents. (C) 2019 Xi'an Jiaotong University. Production and hosting by Elsevier B.V.
资助项目	National Science & Technology Major Project of China 'Key New Drug Creation and Manufacturing Program'[2017ZX09301012-006] ; National Natural Science Foundation of China[81603380] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050306]
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000456828800004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290714]
专题	中国科学院上海药物研究所
通讯作者	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, Chinese Acad Sci, Beijing 100049, Peoples R China 3.Fudan Univ, Shanghai Canc Ctr, Shanghai 200032, Peoples R China 4.Tianjin Univ Tradit Chinese Med, Tianjin, Peoples R China
推荐引用方式 GB/T 7714	Jia, Weiwei,Li, Jing,Du, Feifei,et al. Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study[J]. JOURNAL OF PHARMACEUTICAL ANALYSIS,2019,9(1):25-33.
APA	Jia, Weiwei.,Li, Jing.,Du, Feifei.,Sun, Yan.,Xu, Fang.,...&Li, Chuan.(2019).Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study.JOURNAL OF PHARMACEUTICAL ANALYSIS,9(1),25-33.
MLA	Jia, Weiwei,et al."Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study".JOURNAL OF PHARMACEUTICAL ANALYSIS 9.1(2019):25-33.