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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...

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Autores principales: Le, Thien-Kim, Park, Young Jin, Cha, Gun Su, Oktavia, Fikri A. R. Hardiyanti, Kim, Dong Hyun, Yun, Chul-Ho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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