RT Journal Article
SR Electronic
T1 Metabolism of a selective serotonin and norepinephrine reuptake inhibitor duloxetine in liver microsomes and mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2021-000633
DO 10.1124/dmd.121.000633
A1 Xuan Qin
A1 John M. Hakenjos
A1 Kevin R. MacKenzie
A1 Mercedes Barzi
A1 Hemantkumar Chavan
A1 Pranavanand Nyshadham
A1 Jin Wang
A1 Sung Yun Jung
A1 Joie Z. Guner
A1 Si Chen
A1 Lei Guo
A1 Partha Krishnamurthy
A1 Karl-Dimiter Bissig
A1 Stephen Palmer
A1 Martin M. Matzuk
A1 Feng Li
YR 2021
UL http://dmd.aspetjournals.org/content/early/2021/11/16/dmd.121.000633.abstract
AB 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, thirteen metabolites are novel, including five N-acetyl cysteine adducts and one 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 specie differences were noticed in vitro. The roles of CYP450s in DLX metabolite formation were also verified using human recombinant 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 Current study systematically investigated 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.