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Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism
Tenatoprazole, a newly developed proton pump inhibitor candidate, was developed as an acid inhibitor for gastric acid hypersecretion disorders such as gastric ulcer and reflux esophagitis. It is known that tenatoprazole is metabolized to three major metabolites of 5′-hydroxy tenatoprazole, tenatopra...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863764/ https://www.ncbi.nlm.nih.gov/pubmed/36678652 http://dx.doi.org/10.3390/pharmaceutics15010023 |
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author | Le, Thien-Kim Park, Young Jin Cha, Gun Su Oktavia, Fikri A. R. Hardiyanti Kim, Dong Hyun Yun, Chul-Ho |
author_facet | Le, Thien-Kim Park, Young Jin Cha, Gun Su Oktavia, Fikri A. R. Hardiyanti Kim, Dong Hyun Yun, Chul-Ho |
author_sort | Le, Thien-Kim |
collection | PubMed |
description | Tenatoprazole, a newly developed proton pump inhibitor candidate, was developed as an acid inhibitor for gastric acid hypersecretion disorders such as gastric ulcer and reflux esophagitis. It is known that tenatoprazole is metabolized to three major metabolites of 5′-hydroxy tenatoprazole, tenatoprazole sulfide, and tenatoprazole sulfone in human liver, primarily catalyzed by CYPs 2C19 and 3A4. While CYP2C19 prefers the hydroxylation of tenatoprazole at C-5′ position, CYP3A4 is mainly involved in sulfoxidation reaction to make tenatoprazole sulfone. Tenatoprazole sulfide is a major human metabolite of tenatoprazole and is formed spontaneously and non-enzymatically from tenatoprazole. However, its metabolic fate in the human liver is not fully known. Furthermore, no systematic metabolic study has been performed to study tenatoprazole or tenatoprazole sulfide. Here, we studied the functions of human cytochromes P450 in the metabolic pathway of tenatoprazole and tenatoprazole sulfide by using recombinant human P450s and human liver microsomes. Both CYP 2C19 and CYP3A4 showed distinct regioselective and stereospecific monooxygenation activities toward tenatoprazole and tenatoprazole sulfide. Furthermore, a new major metabolite of tenatoprazole sulfide was found, 1′-N-oxy-5′-hydroxytenatoprzole sulfide, which has never been reported. In conclusion, the metabolic fates of tenatoprazole and tenatoprazole sulfide should be considered in the clinical use of tenatoprazole. |
format | Online Article Text |
id | pubmed-9863764 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98637642023-01-22 Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism Le, Thien-Kim Park, Young Jin Cha, Gun Su Oktavia, Fikri A. R. Hardiyanti Kim, Dong Hyun Yun, Chul-Ho Pharmaceutics Article Tenatoprazole, a newly developed proton pump inhibitor candidate, was developed as an acid inhibitor for gastric acid hypersecretion disorders such as gastric ulcer and reflux esophagitis. It is known that tenatoprazole is metabolized to three major metabolites of 5′-hydroxy tenatoprazole, tenatoprazole sulfide, and tenatoprazole sulfone in human liver, primarily catalyzed by CYPs 2C19 and 3A4. While CYP2C19 prefers the hydroxylation of tenatoprazole at C-5′ position, CYP3A4 is mainly involved in sulfoxidation reaction to make tenatoprazole sulfone. Tenatoprazole sulfide is a major human metabolite of tenatoprazole and is formed spontaneously and non-enzymatically from tenatoprazole. However, its metabolic fate in the human liver is not fully known. Furthermore, no systematic metabolic study has been performed to study tenatoprazole or tenatoprazole sulfide. Here, we studied the functions of human cytochromes P450 in the metabolic pathway of tenatoprazole and tenatoprazole sulfide by using recombinant human P450s and human liver microsomes. Both CYP 2C19 and CYP3A4 showed distinct regioselective and stereospecific monooxygenation activities toward tenatoprazole and tenatoprazole sulfide. Furthermore, a new major metabolite of tenatoprazole sulfide was found, 1′-N-oxy-5′-hydroxytenatoprzole sulfide, which has never been reported. In conclusion, the metabolic fates of tenatoprazole and tenatoprazole sulfide should be considered in the clinical use of tenatoprazole. MDPI 2022-12-21 /pmc/articles/PMC9863764/ /pubmed/36678652 http://dx.doi.org/10.3390/pharmaceutics15010023 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Le, Thien-Kim Park, Young Jin Cha, Gun Su Oktavia, Fikri A. R. Hardiyanti Kim, Dong Hyun Yun, Chul-Ho Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism |
title | Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism |
title_full | Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism |
title_fullStr | Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism |
title_full_unstemmed | Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism |
title_short | Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism |
title_sort | roles of human liver cytochrome p450 enzymes in tenatoprazole metabolism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863764/ https://www.ncbi.nlm.nih.gov/pubmed/36678652 http://dx.doi.org/10.3390/pharmaceutics15010023 |
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