Do antihistamines inhibit CYP2D6 (cytochrome P450 2D6)?

Antihistamines and CYP2D6 Inhibition

First-generation antihistamines like diphenhydramine and chlorpheniramine inhibit CYP2D6, while second-generation antihistamines generally have minimal impact on this enzyme system.

Mechanism of CYP2D6 Inhibition by Antihistamines

First-Generation Antihistamines

• Diphenhydramine is both a substrate and competitive inhibitor of CYP2D6 with an inhibitory constant (Ki) of approximately 2-11 μM 1, 2
• Chlorpheniramine shows similar inhibitory potency with a Ki of approximately 11 μM 1
• Other first-generation antihistamines demonstrate varying degrees of CYP2D6 inhibition:
  • Clemastine: strongest inhibitor (Ki ≈ 2 μM)
  • Hydroxyzine, tripelennamine, promethazine: moderate inhibitors (Ki ≈ 4-6 μM) 1

Second-Generation Antihistamines

• Generally have minimal impact on CYP2D6 metabolism
• The NCCN guidelines specifically note that second-generation antihistamines like citalopram and escitalopram are mild CYP2D6 inhibitors 3, 4

Clinical Significance

Impact on Medications Metabolized by CYP2D6

• CYP2D6 is responsible for metabolizing approximately 25% of prescribed medications 4
• First-generation antihistamines can significantly affect the metabolism of CYP2D6 substrates:
  • Metoprolol: Diphenhydramine decreased metoprolol clearance twofold in CYP2D6 extensive metabolizers 2
  • Tricyclic antidepressants: Inhibition can increase their concentration 3
  • Tamoxifen: Conversion to its active metabolite endoxifen requires CYP2D6 3, 4

Special Considerations for Tamoxifen

• NCCN guidelines specifically caution against using strong CYP2D6 inhibitors in patients taking tamoxifen 3
• "Some SSRIs like fluoxetine and paroxetine decrease the formation of endoxifen, 4-OH tamoxifen, and active metabolites of tamoxifen, and may impact its efficacy" 3

Individual Variability in Response

Genetic Factors

• CYP2D6 ultrarapid metabolizers (1-2% of US population) may experience paradoxical excitation with diphenhydramine 5
• Poor metabolizers may experience increased side effects from antihistamines that are CYP2D6 substrates 6

Drug Interactions

• Concomitant use of other CYP2D6 inhibitors can compound effects:
  • Quinidine (antiarrhythmic): "Inhibits CYP2D6: ↑concentrations of tricyclic antidepressants, metoprolol, antipsychotics; ↓efficacy of codeine" 3
  • Fluoxetine (SSRI): Strong CYP2D6 inhibitor that can interact with antihistamines 7

Clinical Recommendations

1. For patients on medications metabolized by CYP2D6:

   • Prefer second-generation antihistamines over first-generation ones
   • If first-generation antihistamines are needed, monitor for potential drug interactions

2. For patients on tamoxifen:

   • Avoid first-generation antihistamines if possible
   • "Citalopram and venlafaxine appear to have minimal impact on tamoxifen metabolism" 3

3. For patients with known CYP2D6 variations:

   • Ultrarapid metabolizers may experience paradoxical excitation with diphenhydramine 5
   • Poor metabolizers may require lower doses of antihistamines that are CYP2D6 substrates

Common Pitfalls to Avoid

• Assuming all antihistamines have similar effects on CYP2D6
• Overlooking the potential for clinically significant interactions between first-generation antihistamines and commonly prescribed medications
• Failing to consider genetic variations in CYP2D6 activity when patients report unusual responses to antihistamines

In summary, when prescribing antihistamines to patients taking medications metabolized by CYP2D6, second-generation antihistamines are generally preferred due to their minimal impact on this enzyme system.