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

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 sampl...

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Autores principales: Jia, Weiwei, Li, Jing, Du, Feifei, Sun, Yan, Xu, Fang, Wang, Fengqing, Olaleye, Olajide E., Chen, Danghui, Tang, Wei, Zuo, Jianping, Li, Chuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Xi'an Jiaotong University 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355468/
https://www.ncbi.nlm.nih.gov/pubmed/30740254
http://dx.doi.org/10.1016/j.jpha.2018.09.001
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author Jia, Weiwei
Li, Jing
Du, Feifei
Sun, Yan
Xu, Fang
Wang, Fengqing
Olaleye, Olajide E.
Chen, Danghui
Tang, Wei
Zuo, Jianping
Li, Chuan
author_facet Jia, Weiwei
Li, Jing
Du, Feifei
Sun, Yan
Xu, Fang
Wang, Fengqing
Olaleye, Olajide E.
Chen, Danghui
Tang, Wei
Zuo, Jianping
Li, Chuan
author_sort Jia, Weiwei
collection PubMed
description 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.
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spelling pubmed-63554682019-02-08 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 Li, Jing Du, Feifei Sun, Yan Xu, Fang Wang, Fengqing Olaleye, Olajide E. Chen, Danghui Tang, Wei Zuo, Jianping Li, Chuan J Pharm Anal Original Article 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. Xi'an Jiaotong University 2019-02 2018-09-07 /pmc/articles/PMC6355468/ /pubmed/30740254 http://dx.doi.org/10.1016/j.jpha.2018.09.001 Text en © 2018 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Jia, Weiwei
Li, Jing
Du, Feifei
Sun, Yan
Xu, Fang
Wang, Fengqing
Olaleye, Olajide E.
Chen, Danghui
Tang, Wei
Zuo, Jianping
Li, Chuan
Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study
title Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study
title_full Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study
title_fullStr Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study
title_full_unstemmed Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study
title_short Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study
title_sort assay development for determination of dz2002, a new reversible sahh inhibitor, and its acid metabolite dza in blood and application to rat pharmacokinetic study
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355468/
https://www.ncbi.nlm.nih.gov/pubmed/30740254
http://dx.doi.org/10.1016/j.jpha.2018.09.001
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