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 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.

Low plasma serotonin linked to higher nigral iron in Parkinson's disease.

A growing body of evidence suggests nigral iron accumulation plays an important role in the pathophysiology of Parkinson's disease (PD), contributing to dopaminergic neuron loss in the substantia nigra pars compacta (SNc). Converging evidence suggests this accumulation might be related to, or increased by, serotonergic dysfunction, a common, often early feature of the disease. We investigated whether lower plasma serotonin in PD is associated with higher nigral iron. We obtained plasma samples from 97 PD patients and 89 controls and MRI scans from a sub-cohort (62 PD, 70 controls). We measured serotonin concentrations using ultra-high performance liquid chromatography and regional iron content using MRI-based quantitative susceptibility mapping. PD patients had lower plasma serotonin (p < 0.0001) and higher nigral iron content (SNc: p < 0.001) overall. Exclusively in PD, lower plasma serotonin was correlated with higher nigral iron (SNc: r(58) = - 0.501, p < 0.001). This correlation was significant even in patients newly diagnosed (< 1 year) and stronger in the SNc than any other region examined. This study reveals an early, linear association between low serotonin and higher nigral iron in PD patients, which is absent in controls. This is consistent with a serotonin-iron relationship in the disease process, warranting further studies to determine its cause and directionality.