CYP2D6 Intermediate Metabolizer Status and Wellbutrin (Bupropion)
No dose adjustment of bupropion is necessary for CYP2D6 intermediate metabolizers, as bupropion is not metabolized by CYP2D6 and the enzyme does not significantly affect the formation of its active metabolite hydroxybupropion.
Metabolic Pathway of Bupropion
Bupropion is primarily metabolized by CYP2B6, not CYP2D6, to form its major active metabolite hydroxybupropion 1, 2. The formation of hydroxybupropion occurs through hepatic CYP2B6, with this metabolite reaching concentrations 4- to 7-fold higher at steady state compared to the parent drug 1. Two additional active metabolites, threohydrobupropion and erythrohydrobupropion, are formed via non-microsomal pathways rather than through cytochrome P450 enzymes 1.
CYP2D6's Limited Role
Research demonstrates that bupropion plasma levels are not associated with CYP2D6 metabolic status 3. In a study of 12 patients including three poor CYP2D6 metabolizers, plasma level/dose ratios for bupropion, erythrohydrobupropion, and threohydrobupropion showed no association with debrisoquine metabolic status (a marker of CYP2D6 activity) 3.
While hydroxybupropion plasma levels were significantly higher in poor CYP2D6 metabolizers, this represents a secondary effect rather than primary metabolism 3. A larger therapeutic drug monitoring study (n=132) confirmed that CYP2D6 genotype does not significantly alter hydroxybupropion concentrations, though slightly higher bupropion values were observed in poor versus extensive CYP2D6 metabolizers 4.
Standard Dosing Recommendations
Use standard bupropion dosing for CYP2D6 intermediate metabolizers:
- Initial dose: 37.5 mg every morning, then increase by 37.5 mg every 3 days 5
- Maintenance dose: 150 mg twice daily 5
- Maximum dose: 300 mg per day 5
- Give second dose before 3 PM to minimize insomnia risk 5
For sustained-release formulations used in smoking cessation, initiate dosing 1-2 weeks prior to quitting: Days 1-3 at 150 mg once daily, then Days 4 through 12 weeks at 150 mg twice daily if tolerated 5.
Important Clinical Considerations
Bupropion is a strong CYP2D6 inhibitor despite not being metabolized by this enzyme 2, 6. This inhibition occurs through both reversible inhibition and CYP2D6 downregulation at the transcriptional level 6. Therefore, monitor for interactions with other medications metabolized by CYP2D6, regardless of the patient's CYP2D6 metabolizer status 1, 2.
Contraindications include: seizure disorders, brain metastases, concurrent MAO inhibitor use (within 14 days), closed-angle glaucoma, and concomitant tamoxifen use 5.
Genotype That Actually Matters: CYP2B6
If pharmacogenetic testing is available, CYP2B6*6 genotype is clinically relevant for bupropion dosing 4. Homozygous CYP2B6*6 carriers have approximately 50% lower hydroxybupropion concentrations compared to wild-type patients, potentially requiring dose adjustments for therapeutic effect 4. However, CYP2D6 intermediate metabolizer status does not warrant dose modification 3, 4.