Fluoxetine (Prozac) Metabolism
Fluoxetine is primarily metabolized through cytochrome P450 2D6 (CYP2D6) in the liver, with the formation of its active metabolite norfluoxetine, and is subject to genetic variation that can significantly impact drug levels and potential adverse effects. 1, 2
Primary Metabolic Pathway
- Fluoxetine undergoes extensive hepatic metabolism with the primary route being demethylation to form norfluoxetine, its only identified active metabolite 2
- CYP2D6 is the major enzyme responsible for the conversion of fluoxetine to norfluoxetine 1, 3
- Fluoxetine exists as a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers, with the S-fluoxetine enantiomer being eliminated more slowly and predominating in plasma at steady state 2
Secondary Metabolic Pathways
- Beyond CYP2D6, fluoxetine is also metabolized by other CYP enzymes:
Pharmacokinetic Characteristics
- Fluoxetine has a relatively slow elimination half-life of 1-3 days after acute administration and 4-6 days after chronic administration 2
- Norfluoxetine has an even longer elimination half-life of 4-16 days 2
- These long half-lives lead to significant accumulation of both active compounds with chronic use 2
- Fluoxetine metabolism is not proportional to dose, displaying nonlinear pharmacokinetics at therapeutic doses 2, 5
- Approximately 94.5% of fluoxetine is bound to plasma proteins, including albumin and α1-glycoprotein 2
Genetic Variation Impact
- Approximately 7% of the population has reduced CYP2D6 activity and are classified as "poor metabolizers" (PMs) 2
- PMs metabolize S-fluoxetine at a slower rate, achieving higher concentrations of S-fluoxetine and lower concentrations of S-norfluoxetine 2
- PMs are at higher risk of toxicity with fluoxetine due to elevated blood levels 1
- Single-dose fluoxetine at 20 mg shows an area under the curve (AUC) that is 3.9-fold higher in PMs compared to extensive metabolizers (EMs) 1
- At higher doses (60 mg), the difference is even more pronounced, with median AUCs for S- and R-fluoxetine being 11.5- and 2.4-fold higher, respectively, in PMs versus EMs 1
Drug Interactions
- Fluoxetine itself is a potent inhibitor of CYP2D6, converting an average of 43% of EMs to PMs at a long-term dose of 20 mg/day 1
- This inhibitory effect can lead to significant drug interactions with other medications metabolized by CYP2D6 4
- Fluoxetine is also a mechanism-based inhibitor of CYP2C19 3
- The FDA has issued safety labeling changes for fluoxetine regarding increased risk in patients with CYP2D6 PM status or when coadministered with CYP2D6 inhibitors, particularly related to QT prolongation 1
- The inhibitory effects of fluoxetine on CYP enzymes persist long after discontinuation due to the long half-lives of both fluoxetine and norfluoxetine 2, 3
Clinical Implications
- Genetic testing for CYP2D6 status may be valuable for predicting response and adverse effects with fluoxetine treatment 1
- Patients with hepatic impairment show prolonged elimination half-life of fluoxetine and may require dose adjustments 2
- The long elimination half-lives ensure that active drug substances persist in the body for weeks after discontinuation, which is important when considering drug interactions 2
- Higher dosing of fluoxetine (60-80 mg) used in conditions like OCD increases the risk of adverse effects, particularly in CYP2D6 poor metabolizers 1
Monitoring Considerations
- Plasma concentrations of fluoxetine plus norfluoxetine above 500 μg/L appear to be associated with poorer clinical response than lower concentrations 5
- After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine range from 91 to 302 ng/mL and norfluoxetine from 72 to 258 ng/mL 2
- Therapeutic drug monitoring may be particularly valuable in patients with suspected altered metabolism or when drug interactions are a concern 1