Abstract
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.
Footnotes
- Received August 5, 2021.
- Accepted October 12, 2021.
This work was supported by the National Institute of Diabetes and Digestive and Kidney [Grant R01-DK121970] (to F.L.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant R61HD099995] (to F.L.), Cancer Prevention & Research Institute of Texas [Grant RP160805] (to M.M.M.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant P01 HD087157] (to M.M.M.), Bill and Melinda Gates Foundation [INV-001902] (to M.M.M.), and the National Institute of General Medical Sciences [R01-GM115622] (to J.W.). This article is not an official guidance or policy statement of the U.S. FDA. No official support or endorsement by the FDA is intended or should be inferred.
No author has an actual or perceived conflict of interest with the contents of this article.
Dr. Partha Krishnamurthy is deceased.
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