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Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice
Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicit...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Pharmacology and Experimental Therapeutics
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969139/ https://www.ncbi.nlm.nih.gov/pubmed/34785568 http://dx.doi.org/10.1124/dmd.121.000633 |
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author | Qin, Xuan Hakenjos, John M. MacKenzie, Kevin R. Barzi, Mercedes Chavan, Hemantkumar Nyshadham, Pranavanand Wang, Jin Jung, Sung Yun Guner, Joie Z. Chen, Si Guo, Lei Krishnamurthy, Partha Bissig, Karl-Dimiter Palmer, Stephen Matzuk, Martin M. Li, Feng |
author_facet | Qin, Xuan Hakenjos, John M. MacKenzie, Kevin R. Barzi, Mercedes Chavan, Hemantkumar Nyshadham, Pranavanand Wang, Jin Jung, Sung Yun Guner, Joie Z. Chen, Si Guo, Lei Krishnamurthy, Partha Bissig, Karl-Dimiter Palmer, Stephen Matzuk, Martin M. Li, Feng |
author_sort | Qin, Xuan |
collection | PubMed |
description | Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical roles in drug safety and efficacy. However, the metabolic profile of DLX in mice is not available, although mice serve as commonly used animal models for mechanistic studies of drug-induced adverse effects. Our study revealed 39 DLX metabolites in human/mouse liver microsomes and mice. Of note, 13 metabolites are novel, including five N-acetyl cysteine adducts and one reduced glutathione (GSH) adduct associated with DLX. Additionally, the species differences of certain metabolites were observed between human and mouse liver microsomes. CYP1A2 and CYP2D6 are primary enzymes responsible for the formation of DLX metabolites in liver microsomes, including DLX-GSH adducts. In summary, a total of 39 DLX metabolites were identified, and species differences were noticed in vitro. The roles of CYP450s in DLX metabolite formation were also verified using human recombinant cytochrome P450 (P450) enzymes and corresponding chemical inhibitors. Further studies are warranted to address the exact role of DLX metabolism in its adverse effects in vitro (e.g., human primary hepatocytes) and in vivo (e.g., Cyp1a2-null mice). SIGNIFICANCE STATEMENT: This current study systematically investigated Duloxetine (DLX) metabolism and bioactivation in liver microsomes and mice. This study provided a global view of DLX metabolism and bioactivation in liver microsomes and mice, which are very valuable to further elucidate the mechanistic study of DLX-related adverse effects and drug-drug interaction from metabolic aspects. |
format | Online Article Text |
id | pubmed-8969139 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The American Society for Pharmacology and Experimental Therapeutics |
record_format | MEDLINE/PubMed |
spelling | pubmed-89691392022-04-12 Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice Qin, Xuan Hakenjos, John M. MacKenzie, Kevin R. Barzi, Mercedes Chavan, Hemantkumar Nyshadham, Pranavanand Wang, Jin Jung, Sung Yun Guner, Joie Z. Chen, Si Guo, Lei Krishnamurthy, Partha Bissig, Karl-Dimiter Palmer, Stephen Matzuk, Martin M. Li, Feng Drug Metab Dispos Articles Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical roles in drug safety and efficacy. However, the metabolic profile of DLX in mice is not available, although mice serve as commonly used animal models for mechanistic studies of drug-induced adverse effects. Our study revealed 39 DLX metabolites in human/mouse liver microsomes and mice. Of note, 13 metabolites are novel, including five N-acetyl cysteine adducts and one reduced glutathione (GSH) adduct associated with DLX. Additionally, the species differences of certain metabolites were observed between human and mouse liver microsomes. CYP1A2 and CYP2D6 are primary enzymes responsible for the formation of DLX metabolites in liver microsomes, including DLX-GSH adducts. In summary, a total of 39 DLX metabolites were identified, and species differences were noticed in vitro. The roles of CYP450s in DLX metabolite formation were also verified using human recombinant cytochrome P450 (P450) enzymes and corresponding chemical inhibitors. Further studies are warranted to address the exact role of DLX metabolism in its adverse effects in vitro (e.g., human primary hepatocytes) and in vivo (e.g., Cyp1a2-null mice). SIGNIFICANCE STATEMENT: This current study systematically investigated Duloxetine (DLX) metabolism and bioactivation in liver microsomes and mice. This study provided a global view of DLX metabolism and bioactivation in liver microsomes and mice, which are very valuable to further elucidate the mechanistic study of DLX-related adverse effects and drug-drug interaction from metabolic aspects. The American Society for Pharmacology and Experimental Therapeutics 2022-02 2022-02 /pmc/articles/PMC8969139/ /pubmed/34785568 http://dx.doi.org/10.1124/dmd.121.000633 Text en U.S. Government work not protected by U.S. copyright https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the CC BY Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Articles Qin, Xuan Hakenjos, John M. MacKenzie, Kevin R. Barzi, Mercedes Chavan, Hemantkumar Nyshadham, Pranavanand Wang, Jin Jung, Sung Yun Guner, Joie Z. Chen, Si Guo, Lei Krishnamurthy, Partha Bissig, Karl-Dimiter Palmer, Stephen Matzuk, Martin M. Li, Feng Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice |
title | Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice |
title_full | Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice |
title_fullStr | Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice |
title_full_unstemmed | Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice |
title_short | Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice |
title_sort | metabolism of a selective serotonin and norepinephrine reuptake inhibitor duloxetine in liver microsomes and mice |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969139/ https://www.ncbi.nlm.nih.gov/pubmed/34785568 http://dx.doi.org/10.1124/dmd.121.000633 |
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