Metabolic profiling of norepinephrine reuptake inhibitor atomoxetine

Area of Science:

• Pharmacology
• Drug Metabolism
• Toxicology

Background:

• Atomoxetine (ATX), a norepinephrine transporter inhibitor for ADHD, has known adverse effects like liver injury, but its toxicity mechanisms are unclear.
• Drug metabolism via reactive metabolites is a common cause of adverse drug effects, yet ATX bioactivation remains unstudied.
• Understanding ATX metabolism is crucial for elucidating its toxicity and potential drug-drug interactions.

Purpose of the Study:

• To systematically investigate atomoxetine (ATX) metabolism and bioactivation in human, mouse, and rat liver microsomes and in mice.
• To identify novel ATX metabolites and adducts and determine the specific cytochrome P450 (CYP) enzymes involved in their formation.
• To explore species differences in ATX metabolism for better toxicity and drug interaction modeling.

Main Methods:

• Metabolomic approaches were used to analyze ATX metabolism in liver microsomes (human, mouse, rat) and in vivo in mice.
• Chemical inhibitors and recombinant CYP enzymes were employed to identify key enzymes responsible for metabolite formation.
• LC-MS/MS was used for the identification and characterization of ATX metabolites and adducts.

Main Results:

• Thirty-one ATX metabolites and adducts were identified, with 16 being novel.
• Novel metabolites include methoxyamine-trapped aldehydes, cyclization products, detoluene-ATX, and ATX-N-hydroxylation.
• CYP2C8/2B6 form aldehydes, CYP2D6 forms cyclization/detoluene-ATX, and CYP3A4 forms hydroxylamine; species differences were noted.

Conclusions:

• The identified aldehydes are key to understanding ATX-related adverse effects from a metabolic perspective.
• Species-specific metabolite profiles provide valuable insights for predicting ATX toxicity and drug interactions in relevant animal models.
• This research clarifies ATX metabolic pathways and highlights potential reactive metabolites contributing to its toxicity.