Cargando…
The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice
Duloxetine (DLX) is widely used to treat major depressive disorder. Little is known about the mechanistic basis for DLX-related adverse effects (e.g., liver injury). Human CYP1A2 and CYP2D6 mainly contributes to DLX metabolism, which was proposed to be involved in its adverse effects. Here, we inves...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10395004/ https://www.ncbi.nlm.nih.gov/pubmed/36513193 http://dx.doi.org/10.1016/j.ejps.2022.106358 |
_version_ | 1785083497680994304 |
---|---|
author | Qin, Xuan Xie, Cen Hakenjos, John M. MacKenzie, Kevin R. Boyd, Shelton R. Barzi, Mercedes Bissig, Karl-Dimiter Young, Damian W. Li, Feng |
author_facet | Qin, Xuan Xie, Cen Hakenjos, John M. MacKenzie, Kevin R. Boyd, Shelton R. Barzi, Mercedes Bissig, Karl-Dimiter Young, Damian W. Li, Feng |
author_sort | Qin, Xuan |
collection | PubMed |
description | Duloxetine (DLX) is widely used to treat major depressive disorder. Little is known about the mechanistic basis for DLX-related adverse effects (e.g., liver injury). Human CYP1A2 and CYP2D6 mainly contributes to DLX metabolism, which was proposed to be involved in its adverse effects. Here, we investigated the roles of Cyp1a2 and Cyp2d on DLX pharmacokinetic profile and tissue distribution using a Cyp1a2 knockout (Cyp1a2-KO) mouse model together with a Cyp2d inhibitor (propranolol). Cyp1a2-KO has the few effects on the systematic exposure (area under the plasma concentration–time curve, AUC) and tissue disposition of DLX and its primary metabolites. Propranolol dramatically increased the AUCs of DLX by 3 folds and 1.5 folds in WT and Cyp1a2-KO mice, respectively. Meanwhile, Cyp2d inhibitor decreased the AUC of Cyp2d-involved DLX metabolites (e.g., M16). Mouse tissue distribution revealed that DLX and its major metabolites were the most abundant in kidney, followed by liver and lung with/without Cyp2d inhibitor. Cyp2d inhibitor significantly increased DLX levels in tissues (e.g., liver) in WT and KO mice and decreases the levels of M3, M15, M16 and M17, while it increased the levels of M4, M28 and M29 in tissues. Our findings indicated that Cyp2d play a fundamental role on DLX pharmacokinetic profile and tissue distribution in mice. Clinical studies suggested that CYP1A2 has more effects on DLX systemic exposure than CYP2D6. Further studies in liver humanized mice or clinical studies concerning CYP2D6 inhibitors-DLX interaction study could clarify the roles of CYP2D6 on DLX pharmacokinetics and toxicity in human. |
format | Online Article Text |
id | pubmed-10395004 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-103950042023-08-02 The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice Qin, Xuan Xie, Cen Hakenjos, John M. MacKenzie, Kevin R. Boyd, Shelton R. Barzi, Mercedes Bissig, Karl-Dimiter Young, Damian W. Li, Feng Eur J Pharm Sci Article Duloxetine (DLX) is widely used to treat major depressive disorder. Little is known about the mechanistic basis for DLX-related adverse effects (e.g., liver injury). Human CYP1A2 and CYP2D6 mainly contributes to DLX metabolism, which was proposed to be involved in its adverse effects. Here, we investigated the roles of Cyp1a2 and Cyp2d on DLX pharmacokinetic profile and tissue distribution using a Cyp1a2 knockout (Cyp1a2-KO) mouse model together with a Cyp2d inhibitor (propranolol). Cyp1a2-KO has the few effects on the systematic exposure (area under the plasma concentration–time curve, AUC) and tissue disposition of DLX and its primary metabolites. Propranolol dramatically increased the AUCs of DLX by 3 folds and 1.5 folds in WT and Cyp1a2-KO mice, respectively. Meanwhile, Cyp2d inhibitor decreased the AUC of Cyp2d-involved DLX metabolites (e.g., M16). Mouse tissue distribution revealed that DLX and its major metabolites were the most abundant in kidney, followed by liver and lung with/without Cyp2d inhibitor. Cyp2d inhibitor significantly increased DLX levels in tissues (e.g., liver) in WT and KO mice and decreases the levels of M3, M15, M16 and M17, while it increased the levels of M4, M28 and M29 in tissues. Our findings indicated that Cyp2d play a fundamental role on DLX pharmacokinetic profile and tissue distribution in mice. Clinical studies suggested that CYP1A2 has more effects on DLX systemic exposure than CYP2D6. Further studies in liver humanized mice or clinical studies concerning CYP2D6 inhibitors-DLX interaction study could clarify the roles of CYP2D6 on DLX pharmacokinetics and toxicity in human. 2023-02-01 2022-12-10 /pmc/articles/PMC10395004/ /pubmed/36513193 http://dx.doi.org/10.1016/j.ejps.2022.106358 Text en https://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/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Qin, Xuan Xie, Cen Hakenjos, John M. MacKenzie, Kevin R. Boyd, Shelton R. Barzi, Mercedes Bissig, Karl-Dimiter Young, Damian W. Li, Feng The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice |
title | The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice |
title_full | The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice |
title_fullStr | The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice |
title_full_unstemmed | The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice |
title_short | The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice |
title_sort | roles of cyp1a2 and cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10395004/ https://www.ncbi.nlm.nih.gov/pubmed/36513193 http://dx.doi.org/10.1016/j.ejps.2022.106358 |
work_keys_str_mv | AT qinxuan therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT xiecen therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT hakenjosjohnm therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT mackenziekevinr therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT boydsheltonr therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT barzimercedes therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT bissigkarldimiter therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT youngdamianw therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT lifeng therolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT qinxuan rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT xiecen rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT hakenjosjohnm rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT mackenziekevinr rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT boydsheltonr rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT barzimercedes rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT bissigkarldimiter rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT youngdamianw rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice AT lifeng rolesofcyp1a2andcyp2dinpharmacokineticprofilesofserotoninandnorepinephrinereuptakeinhibitorduloxetineanditsmetabolitesinmice |