Wellbutrin Dosing for CYP2D6 Intermediate Metabolizers
For CYP2D6 intermediate metabolizers taking Wellbutrin (bupropion), use standard dosing protocols without adjustment, as bupropion is primarily metabolized by CYP2B6, not CYP2D6. 1, 2
Key Pharmacokinetic Principle
- Bupropion is metabolized primarily by CYP2B6 to form its active metabolite hydroxybupropion, not by CYP2D6 2, 3
- CYP2D6 metabolizer status does not affect bupropion clearance or exposure 2
- The CYP2D6 intermediate metabolizer genotype is therefore not relevant for bupropion dose adjustments 2, 3
Standard Dosing Recommendations
For Major Depressive Disorder:
- Start with 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total daily) of the SR formulation 1
- For XL formulation: start 150 mg once daily, increase to 300 mg once daily as maintenance 1
- Maximum dose: 400 mg/day for SR; 450 mg/day for XL 1
For Smoking Cessation:
- 150 mg twice daily (300 mg total) of SR formulation 1
- Begin dosing 1-2 weeks before target quit date 1
- Treatment duration: 7-12 weeks 1
Critical Clinical Consideration: Bupropion as CYP2D6 Inhibitor
The important interaction runs in the opposite direction: bupropion is a potent CYP2D6 inhibitor, not a CYP2D6 substrate 3, 4. This means:
- Bupropion inhibits CYP2D6 in a dose-dependent manner 4
- At 150 mg/day: 19% of patients are phenoconverted to CYP2D6 poor metabolizers 4
- At ≥300 mg/day: 50% of patients are phenoconverted to CYP2D6 poor metabolizers 4
Practical Implications:
- If the patient is taking other medications metabolized by CYP2D6 (e.g., venlafaxine, tricyclic antidepressants, metoprolol, codeine), those drugs may require dose reduction 3, 4
- The patient's baseline CYP2D6 intermediate metabolizer status makes them more vulnerable to complete CYP2D6 inhibition when bupropion is added 4
- Consider therapeutic drug monitoring for CYP2D6 substrate medications during bupropion comedication 4
Dose Adjustments That Actually Matter
Adjust bupropion doses for these conditions only:
- Hepatic impairment (moderate to severe): maximum 150 mg daily total 1
- Renal impairment (moderate to severe, GFR <90 mL/min): reduce total daily dose by 50% 1
- Older adults: start with 37.5 mg every morning, increase by 37.5 mg every 3 days as tolerated, maximum 300 mg/day 1
Safety Monitoring
- Seizure risk: maximum dose should not exceed 450 mg/day; contraindicated in seizure disorders 1
- Blood pressure monitoring: bupropion should be avoided in uncontrolled hypertension 1
- Timing of second dose: administer before 3 PM to minimize insomnia risk 1
- Neuropsychiatric effects: monitor especially in patients <24 years old 1