What are known inhibitors of the CYP2D6 (cytochrome P450 2D6) enzyme?

Known Inhibitors of CYP2D6

Paroxetine and fluoxetine are the most potent CYP2D6 inhibitors among SSRIs, while desvenlafaxine has minimal to no CYP2D6 inhibition, making it the preferred choice when CYP2D6 interactions are a concern. 1

Classification of CYP2D6 Inhibitors

Strong CYP2D6 Inhibitors

• SSRIs/SNRIs:
  • Paroxetine (strongest inhibitor, Ki = 0.15 μM) 2
  • Fluoxetine (Ki = 0.60 μM) 2
  • Norfluoxetine (active metabolite of fluoxetine, Ki = 0.43 μM) 2
  • Bupropion 3
  • Duloxetine 4

Moderate CYP2D6 Inhibitors

• Sertraline (Ki = 0.70 μM) 2
• Fluvoxamine (Ki = 8.2 μM) 2

Weak CYP2D6 Inhibitors

• Citalopram (Ki = 5.1 μM) 2
• Escitalopram 4
• Venlafaxine 1

Minimal/No CYP2D6 Inhibition

• Desvenlafaxine 1

Clinical Significance of CYP2D6 Inhibition

CYP2D6 is responsible for metabolizing approximately 25% of all prescribed medications, and inhibition can lead to:

1. Increased plasma concentrations of medications metabolized by CYP2D6 1
2. Reduced efficacy of prodrugs requiring CYP2D6 activation (e.g., tamoxifen to endoxifen) 4
3. Phenocopying - converting normal or intermediate metabolizers into functional poor metabolizers 4

Important Drug-Drug Interactions

Tamoxifen and CYP2D6 Inhibitors

• Tamoxifen requires CYP2D6 for conversion to its active metabolite endoxifen 4
• Strong CYP2D6 inhibitors like paroxetine and fluoxetine can significantly reduce tamoxifen efficacy 4
• Clinical studies indicate increased risk of breast cancer recurrence in patients treated with tamoxifen and strong CYP2D6 inhibitors 4
• Recommendation: Avoid strong CYP2D6 inhibitors in patients on tamoxifen; prefer desvenlafaxine or venlafaxine if an antidepressant is needed 1

Other Notable CYP2D6 Substrate Interactions

• Tricyclic antidepressants: Increased plasma levels when combined with CYP2D6 inhibitors 2
• Antipsychotics: Increased risk of side effects (e.g., haloperidol, risperidone, thioridazine) 3
• Beta-blockers: Increased plasma levels (e.g., metoprolol) 3
• Type 1C antiarrhythmics: Increased risk of toxicity (e.g., propafenone, flecainide) 3

Duration of CYP2D6 Inhibition

• After short-term paroxetine treatment (6 weeks), CYP2D6 activity normalizes within 4 weeks of discontinuation 5
• After long-term paroxetine treatment (average 18.7 weeks), CYP2D6 activity may remain inhibited beyond 6 weeks in some patients 5

Clinical Recommendations

1. For patients on tamoxifen:

   • Avoid strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion)
   • If antidepressant therapy is needed, prefer desvenlafaxine (minimal CYP2D6 inhibition) or mild inhibitors (citalopram, escitalopram, sertraline, venlafaxine) 4, 1

2. For patients on multiple medications:

   • Review all medications for potential CYP2D6 interactions
   • Consider alternatives to strong CYP2D6 inhibitors when possible
   • Allow sufficient washout period (at least 4 weeks, preferably longer after extended use) when switching from strong CYP2D6 inhibitors 5

3. For patients with known CYP2D6 poor metabolizer status:

   • Avoid adding CYP2D6 inhibitors that could further impair metabolism
   • Consider dose reductions for CYP2D6 substrates 6

Common Pitfalls

• Failing to recognize that drug-drug interactions via CYP2D6 can be as impactful as genetic polymorphisms 7
• Overlooking the long half-life of fluoxetine and its active metabolite norfluoxetine, which can inhibit CYP2D6 for weeks after discontinuation
• Not accounting for the cumulative effect of multiple weak CYP2D6 inhibitors
• Assuming all SSRIs/SNRIs have similar effects on CYP2D6, when they vary significantly in inhibitory potency 8