Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice

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.

The Antidepressant Duloxetine Inhibits Platelet Function and Protects against Thrombosis

“…Of note, based on these data and the fact that 35 µM of duloxetine has the capacity to exert significant inhibitory effects on platelet function regardless of the platelet function assay and/or agonist used, this dose was selected for further in vitro experimentation. Following this, we examined its ex vivo effects by injecting mice with 20 mg/kg of duloxetine, which was selected based on a literature review [ 16 , 17 , 18 , 19 , 20 , 21 ], before platelets were collected and their aggregation response examined. Indeed, duloxetine significantly reduced ADP- (58% ± 13), and U46619 (43% ± 11)-induced platelet aggregation ( Figure 1 C,D, respectively).…”

Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-induced Peripheral Neurotoxicity

“…On the basis of a VFH test to evaluate mechanical allodynia, we found that a single dose of duloxetine given before oxaliplatin is sufficient to offer complete protection against both acute and chronic forms OIPN in wild-type mice in a manner that resembles observations made in OCT1/2(−/−) mice. Compared with the parent drug, the major duloxetine metabolites 5-hydroxy-6-methoxyduloxetine and 4-hydroxy-duloxetine-glucuronide (23) were found to display only weak OCT2-inhibitory properties, suggesting that the in vivo findings are likely mediated by duloxetine itself. The recorded nerve conduction amplitudes and velocities were not affected by oxaliplatin treatment in the applied murine model, and these measures were not further influenced by duloxetine pre-treatment.…”

Identifying the Reactive Metabolites of Tyrosine Kinase Inhibitor Pexidartinib In Vitro Using LC–MS-Based Metabolomic Approaches

“…Metabolomics-based strategies have been widely adopted for studying both stable and reactive drug metabolites. − , Reactive drug metabolites are well appreciated as significant contributors to drug adverse effects due to their potential for covalent modification of important biological macromolecules such as proteins and DNA. , Comprehensive understanding of the metabolic profile and characterizing reactive metabolites of drug benefit drug safety evaluation and improvement. In our previous work, we identified stable phase I metabolites of PEX, indicating extensive CYP3A-mediated metabolism of PEX in vitro .…”