The Roles of Cyp1a2 and Cyp2d in Pharmacokinetic Profiles of Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine and Its Metabolites in Mice

Authors

Xuan Qin
Cen Xie
John M Hakenjos
Kevin R MacKenzie
Shelton R Boyd
Mercedes Barzi
Karl-Dimiter Bissig
Damian W Young
Feng Li

Publication Date

2-1-2023

Journal

European Journal of Pharmaceutical Sciences

DOI

10.1016/j.ejps.2022.106358

PMID

36513193

PMCID

PMC10395004

PubMedCentral® Posted Date

8-2-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Mice, Animals, Duloxetine Hydrochloride, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP2D6, Serotonin and Noradrenaline Reuptake Inhibitors, Depressive Disorder, Major, Propranolol, Serotonin, Central Nervous System Agents, Mice, Knockout, Duloxetine, Cyp1a2-knockout mouse, Cyp2d inhibitor, Pharmacokinetics, Tissue distribution

Abstract

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.

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