What are CYP2D6 (cytochrome P450 2D6) medications?

CYP2D6 Medications: Substrates, Inhibitors, and Clinical Significance

CYP2D6 medications are drugs that are either metabolized by the cytochrome P450 2D6 enzyme or inhibit its function, with significant implications for drug efficacy, toxicity, and interactions.

Medications Metabolized by CYP2D6 (Substrates)

CYP2D6 is responsible for metabolizing approximately 25% of currently prescribed medications 1, despite comprising only 2-4% of hepatic cytochrome P450 enzymes. Key drug classes metabolized by CYP2D6 include:

• Antidepressants:

  • Tricyclic antidepressants (especially secondary amines like desipramine)
  • Selective serotonin reuptake inhibitors (SSRIs) including fluoxetine and paroxetine
  • Venlafaxine

• Antipsychotics:

  • Phenothiazines
  • Risperidone

• Cardiovascular medications:

  • Antiarrhythmics (e.g., flecainide, propafenone, encainide)
  • Beta-blockers (especially metoprolol, less so for carvedilol, propranolol, timolol)

• Opioids:

  • Codeine (conversion to morphine)
  • Tramadol

• Other medications:

  • Tamoxifen (conversion to active metabolite endoxifen)
  • Atomoxetine

Medications that Inhibit CYP2D6

Several medications can inhibit CYP2D6 activity, potentially affecting the metabolism of CYP2D6 substrates. The rank order of potency for SSRIs as CYP2D6 inhibitors is 2, 3:

• Paroxetine (strongest inhibitor)
• Fluoxetine and its metabolite norfluoxetine
• Sertraline (moderate inhibitor)
• Fluvoxamine (weaker inhibitor)
• Venlafaxine (weakest inhibitor)
• Citalopram (minimal inhibition)

Clinical Significance of CYP2D6 Metabolism

Genetic Polymorphism and Metabolizer Status

CYP2D6 activity varies considerably within populations due to genetic polymorphism 4, 1:

• Poor Metabolizers (PM): Have no functional CYP2D6 activity due to null alleles (*3, *4, *5, *6, etc.)
• Intermediate Metabolizers (IM): Have reduced enzyme activity
• Extensive Metabolizers (EM): Have normal enzyme function
• Ultrarapid Metabolizers (UM): Have increased enzyme activity due to gene duplication

Clinical Implications

1. Risk of toxicity:

   • Poor metabolizers may experience elevated blood levels and increased side effects with standard doses of CYP2D6 substrates 4
   • For example, CYP2D6 poor metabolizers are at higher risk of toxicity with fluoxetine, paroxetine, and venlafaxine 4

2. Reduced efficacy:

   • Some medications require CYP2D6 activation to produce therapeutic effects
   • Example: Tamoxifen requires CYP2D6 metabolism to produce its active metabolite endoxifen; inhibition of CYP2D6 by paroxetine may reduce tamoxifen efficacy 5

3. Drug interactions:

   • Co-administration of CYP2D6 substrates with inhibitors can lead to significant interactions
   • Example: Paroxetine or fluoxetine can increase desipramine levels 3-4 fold 2
   • The FDA label for paroxetine warns about interactions with other CYP2D6 substrates 5

4. Endoxifen levels in breast cancer treatment:

   • The NCCN guidelines recommend avoiding potent CYP2D6 inhibitors (particularly paroxetine and fluoxetine) in patients taking tamoxifen 4

Practical Considerations

1. Dose adjustments:

   • For known CYP2D6 poor metabolizers, lower starting doses may be appropriate for CYP2D6 substrates 6
   • When adding a CYP2D6 inhibitor to a patient already taking a CYP2D6 substrate, dose reduction of the substrate may be necessary

2. Monitoring:

   • Increased monitoring for side effects when combining CYP2D6 inhibitors with substrates
   • Particular caution with narrow therapeutic index drugs

3. Alternative medications:

   • Consider alternatives to potent CYP2D6 inhibitors when patients are taking CYP2D6 substrates
   • For example, when prescribing an SSRI for patients on tamoxifen, citalopram, escitalopram, or sertraline may be preferred over paroxetine or fluoxetine 4

Common Pitfalls

• Overlooking the persistence of inhibition: Fluoxetine's active metabolite norfluoxetine has a long half-life, causing CYP2D6 inhibition to persist for weeks after discontinuation 2
• Assuming all drugs in a class have similar effects: Within drug classes (e.g., beta-blockers, SSRIs), there are significant differences in CYP2D6 dependency and inhibition potential
• Ignoring phenocopying: Some patients may appear to be poor metabolizers due to drug inhibition rather than genetics (phenocopying)

Understanding CYP2D6 metabolism is crucial for optimizing drug therapy, minimizing adverse effects, and ensuring therapeutic efficacy, particularly for medications with narrow therapeutic indices or those requiring metabolic activation.