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

作　　者：Weiwei Jia Jing Li Feifei Du Yan Sun Fang Xu Fengqing Wang Olajide E.Olaleye Danghui Chen Wei Tang Jianping Zuo Chuan Li 

机构地区：[1]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences [2]University of Chinese Academy of Sciences, Chinese Academy of Sciences [3]Fudan University Shanghai Cancer Center

出　　处：《Journal of Pharmaceutical Analysis》2019年第1期25-33,共9页药物分析学报（英文版）

基　　金：funded by grants from the National Science & Technology Major Project of China ‘Key New Drug Creation and Manufacturing Program’ (2017ZX09301012-006);the National Natural Science Foundation of China (81603380);the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12050306)

摘　　要：Methyl(S)-4-(6-amino-9 H-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-9 H-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.Methyl(S)-4-(6-amino-9 H-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-9 H-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.

关 键 词：S-adenosyl-L-homocysteine HYDROLASE DZ2002 CARBOXYLESTERASES PHARMACOKINETICS 

分 类 号：R[医药卫生]