Metabolism of Strattera and Wellbutrin
Both Strattera (atomoxetine) and Wellbutrin (bupropion) are primarily metabolized by the liver.
Hepatic Metabolism Pathway
Atomoxetine (Strattera)
- Atomoxetine undergoes extensive hepatic biotransformation through three oxidative pathways: aromatic ring-hydroxylation, benzylic hydroxylation, and N-demethylation 1, 2
- The primary metabolic pathway is aromatic ring-hydroxylation, which forms 4-hydroxyatomoxetine, mediated predominantly by the cytochrome P450 (CYP) 2D6 enzyme 2
- The formed 4-hydroxyatomoxetine is subsequently glucuronidated in the liver and excreted in urine 2
- Patients with hepatic insufficiency show significantly increased atomoxetine exposure due to impaired hepatic metabolism 1
Bupropion (Wellbutrin)
- Bupropion is a dopamine/norepinephrine reuptake inhibitor that undergoes hepatic metabolism through the cytochrome P450 enzyme system 3
- The liver serves as the primary site for bupropion's extensive biotransformation 3
Clinical Implications of Hepatic Metabolism
CYP2D6 Polymorphism Effects (Atomoxetine)
- CYP2D6 extensive metabolizers have an atomoxetine plasma half-life of 5.2 hours with systemic clearance of 0.35 L/h/kg 2
- CYP2D6 poor metabolizers have a significantly prolonged half-life of 21.6 hours with reduced clearance of 0.03 L/h/kg 2
- Poor metabolizers experience approximately 10-fold higher steady-state plasma concentrations compared to extensive metabolizers 2
- CYP2D6 inhibitors (such as paroxetine) produce pharmacokinetic changes in extensive metabolizers similar to those seen in poor metabolizers 1, 2
Hepatic Insufficiency Considerations
- Hepatic insufficiency significantly affects the elimination of both medications, requiring dose adjustments 4
- The liver's role in drug metabolism is far more significant than renal metabolism for these agents 4, 5
Important Clinical Caveats
- While most drug metabolism occurs in the liver, cytochrome P450 enzymes are also present in extrahepatic sites including the gastrointestinal mucosa, kidney, lung, and brain 6, 5
- However, the liver remains the major organ responsible for the metabolism of both atomoxetine and bupropion 6, 5, 7
- Drug-metabolizing enzyme activity can be significantly altered in chronic liver diseases, including nonalcoholic fatty liver disease, potentially affecting clearance and increasing risk of adverse drug reactions 7