Are atomoxetine and fluoxetine (selective serotonin reuptake inhibitor) metabolized through the liver?

Are Both Medications Metabolized Through the Liver?

Yes, both atomoxetine and fluoxetine are extensively metabolized through the liver via cytochrome P450 enzyme pathways, with atomoxetine primarily metabolized by CYP2D6 and fluoxetine also primarily metabolized by CYP2D6 to form its active metabolite norfluoxetine. 1, 2, 3, 4

Atomoxetine Hepatic Metabolism

Atomoxetine undergoes extensive hepatic metabolism primarily through the CYP2D6 enzymatic pathway. 1, 3

• The drug is metabolized to its major oxidative metabolite, 4-hydroxyatomoxetine, which is then glucuronidated 3
• Only a small fraction (less than 3%) is excreted unchanged in urine, indicating extensive biotransformation in the liver 3
• Mean apparent plasma clearance in extensive metabolizers is 0.35 L/hr/kg with a half-life of 5.2 hours, while poor metabolizers have clearance of 0.03 L/hr/kg with a half-life of 21.6 hours 3
• Approximately 7% of the population are poor CYP2D6 metabolizers, resulting in 10-fold higher AUC and 5-fold higher peak concentrations 1, 3

Fluoxetine Hepatic Metabolism

Fluoxetine is extensively metabolized in the liver, primarily through CYP2D6, to form its active metabolite norfluoxetine. 2, 4

• The primary metabolic pathway involves demethylation by CYP2D6 to produce norfluoxetine, the only identified active metabolite 4
• The primary route of elimination is hepatic metabolism to inactive metabolites that are then excreted by the kidney 4
• Poor CYP2D6 metabolizers (approximately 7% of the population) achieve 3.9-fold higher AUC at 20 mg doses, and at 60 mg doses, the difference is even more pronounced with 11.5-fold higher levels for S-fluoxetine 2
• Fluoxetine itself is a potent CYP2D6 inhibitor, converting approximately 43% of extensive metabolizers to poor metabolizers at 20 mg/day 2, 5

Critical Drug Interaction Between These Medications

When fluoxetine and atomoxetine are coadministered, fluoxetine's potent CYP2D6 inhibition substantially increases atomoxetine plasma exposure, requiring dosage adjustment. 1, 3

• Coadministration with potent CYP2D6 inhibitors like fluoxetine results in atomoxetine exposure similar to that seen in poor metabolizers 3
• This interaction can lead to significantly higher atomoxetine levels, increasing the risk of adverse effects including cardiovascular effects and decreased appetite 1, 6
• Dosing adjustment is necessary when these medications are combined 3

Clinical Implications for Hepatic Impairment

Patients with hepatic impairment require dose reduction for atomoxetine due to decreased clearance. 7

• Initial target doses should be reduced to 50% of normal dose for moderate hepatic impairment and 25% for severe hepatic impairment 7
• Systemic clearance of atomoxetine is significantly reduced in hepatic impairment, resulting in increased exposure (AUC 1.58 versus 0.85 μg·h⁻¹·mL⁻¹) 7