Cargando…
Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways
BACKGROUND: Enflicoxib is a non-steroidal anti-inflammatory drug of the coxib family characterized by a long-lasting pharmacological activity that has been attributed to its active metabolite E-6132. OBJECTIVES: The aim of this work was to explore enflicoxib biotransformation in vitro in humans, rat...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Bentham Science Publishers
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175088/ https://www.ncbi.nlm.nih.gov/pubmed/34886785 http://dx.doi.org/10.2174/1872312814666211209161933 |
_version_ | 1784722380632883200 |
---|---|
author | Solà, Josep Menargues, Àngel Homedes, Josep Salichs, Marta Serafini, Maria Teresa Encina, Gregorio |
author_facet | Solà, Josep Menargues, Àngel Homedes, Josep Salichs, Marta Serafini, Maria Teresa Encina, Gregorio |
author_sort | Solà, Josep |
collection | PubMed |
description | BACKGROUND: Enflicoxib is a non-steroidal anti-inflammatory drug of the coxib family characterized by a long-lasting pharmacological activity that has been attributed to its active metabolite E-6132. OBJECTIVES: The aim of this work was to explore enflicoxib biotransformation in vitro in humans, rats and dogs, and to determine its metabolic pathways. METHODS: Different in vitro test systems were used, including hepatocytes and liver and non-hepatic microsomes. The samples were incubated with enflicoxib and/or any of its metabolites at 37°C for different times depending on the test system. The analyses were performed by liquid chromatography coupled with either radioactivity detection or high-resolution mass spectrometry. RESULTS: Enflicoxib was efficiently metabolized by cytochrome P-450 into three main phase I metabolites: M8, E-6132, and M7. The non-active hydroxy-pyrazoline metabolite M8 accounted for most of the fraction metabolized in all the three species. The active pyrazol metabolite E-6132 showed a slow formation rate, especially in dogs, whereas metabolite M7 was a secondary metabolite formed by oxidation of M8. In hepatocytes, diverse phase II metabolite conjugates were formed, including enflicoxib glucuronide, M8 glucuronide, E-6132 glucuronide, M7 glucuronide, and M7 sulfate. Metabolite E-6132 was most probably eliminated by a unique glucuronidation reaction at a very low rate. CONCLUSION: The phase I metabolism of enflicoxib was qualitatively very similar among rats, humans and dogs. The low formation and glucuronidation rates of the active enflicoxib metabolite E-6132 in dogs are postulated as key factors underlying the mechanism of its long-lasting pharmacokinetics and enflicoxib's overall sustained efficacy. |
format | Online Article Text |
id | pubmed-9175088 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Bentham Science Publishers |
record_format | MEDLINE/PubMed |
spelling | pubmed-91750882022-06-27 Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways Solà, Josep Menargues, Àngel Homedes, Josep Salichs, Marta Serafini, Maria Teresa Encina, Gregorio Drug Metab Lett Article BACKGROUND: Enflicoxib is a non-steroidal anti-inflammatory drug of the coxib family characterized by a long-lasting pharmacological activity that has been attributed to its active metabolite E-6132. OBJECTIVES: The aim of this work was to explore enflicoxib biotransformation in vitro in humans, rats and dogs, and to determine its metabolic pathways. METHODS: Different in vitro test systems were used, including hepatocytes and liver and non-hepatic microsomes. The samples were incubated with enflicoxib and/or any of its metabolites at 37°C for different times depending on the test system. The analyses were performed by liquid chromatography coupled with either radioactivity detection or high-resolution mass spectrometry. RESULTS: Enflicoxib was efficiently metabolized by cytochrome P-450 into three main phase I metabolites: M8, E-6132, and M7. The non-active hydroxy-pyrazoline metabolite M8 accounted for most of the fraction metabolized in all the three species. The active pyrazol metabolite E-6132 showed a slow formation rate, especially in dogs, whereas metabolite M7 was a secondary metabolite formed by oxidation of M8. In hepatocytes, diverse phase II metabolite conjugates were formed, including enflicoxib glucuronide, M8 glucuronide, E-6132 glucuronide, M7 glucuronide, and M7 sulfate. Metabolite E-6132 was most probably eliminated by a unique glucuronidation reaction at a very low rate. CONCLUSION: The phase I metabolism of enflicoxib was qualitatively very similar among rats, humans and dogs. The low formation and glucuronidation rates of the active enflicoxib metabolite E-6132 in dogs are postulated as key factors underlying the mechanism of its long-lasting pharmacokinetics and enflicoxib's overall sustained efficacy. Bentham Science Publishers 2021-12-29 2021-12-29 /pmc/articles/PMC9175088/ /pubmed/34886785 http://dx.doi.org/10.2174/1872312814666211209161933 Text en © 2021 Bentham Science Publishers https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. |
spellingShingle | Article Solà, Josep Menargues, Àngel Homedes, Josep Salichs, Marta Serafini, Maria Teresa Encina, Gregorio Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways |
title | Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways |
title_full | Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways |
title_fullStr | Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways |
title_full_unstemmed | Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways |
title_short | Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways |
title_sort | comparative in vitro metabolism of enflicoxib in dogs, rats, and humans: main metabolites and proposed metabolic pathways |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175088/ https://www.ncbi.nlm.nih.gov/pubmed/34886785 http://dx.doi.org/10.2174/1872312814666211209161933 |
work_keys_str_mv | AT solajosep comparativeinvitrometabolismofenflicoxibindogsratsandhumansmainmetabolitesandproposedmetabolicpathways AT menarguesangel comparativeinvitrometabolismofenflicoxibindogsratsandhumansmainmetabolitesandproposedmetabolicpathways AT homedesjosep comparativeinvitrometabolismofenflicoxibindogsratsandhumansmainmetabolitesandproposedmetabolicpathways AT salichsmarta comparativeinvitrometabolismofenflicoxibindogsratsandhumansmainmetabolitesandproposedmetabolicpathways AT serafinimariateresa comparativeinvitrometabolismofenflicoxibindogsratsandhumansmainmetabolitesandproposedmetabolicpathways AT encinagregorio comparativeinvitrometabolismofenflicoxibindogsratsandhumansmainmetabolitesandproposedmetabolicpathways |