Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1783391337909846016 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6355468 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Xi'an Jiaotong University |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT jiaweiwei assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT lijing assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT dufeifei assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT sunyan assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT xufang assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT wangfengqing assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT olaleyeolajidee assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT chendanghui assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT tangwei assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT zuojianping assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy AT lichuan assaydevelopmentfordeterminationofdz2002anewreversiblesahhinhibitoranditsacidmetabolitedzainbloodandapplicationtoratpharmacokineticstudy |