Does Diphenhydramine Inhibit CYP2D6?
Yes, diphenhydramine is a clinically significant inhibitor of CYP2D6, with documented in vitro inhibitory constant (Ki) values of approximately 2-11 μM and proven capacity to reduce CYP2D6-mediated drug metabolism by 50-60% in vivo at therapeutic doses.
Mechanism and Potency of Inhibition
Diphenhydramine functions as both a competitive inhibitor and a high-affinity substrate of CYP2D6, with a Ki of approximately 2 μM in vitro and a Km of 1.12 μM for its own N-demethylation 1, 2.
The drug demonstrates mild to moderate inhibitory potency compared to other antihistamines, with estimated Ki values ranging from 2-11 μM depending on the substrate tested 1.
CYP2D6 is the primary enzyme responsible for diphenhydramine's N-demethylation pathway, making this a bidirectional interaction where diphenhydramine both inhibits and is metabolized by CYP2D6 2.
Clinical Evidence of Drug Interactions
Metoprolol Interaction
In extensive metabolizers (those with normal CYP2D6 activity), diphenhydramine at 50 mg every 12 hours decreased metoprolol oral clearance by 50% (from 104 L/hr to 43 L/hr) and prolonged its negative chronotropic and inotropic cardiac effects 3.
This interaction was absent in CYP2D6 poor metabolizers, confirming the CYP2D6-specific mechanism 3.
Venlafaxine Interaction
Diphenhydramine reduced venlafaxine oral clearance by approximately 60% in extensive metabolizers (from 104 L/hr to 43 L/hr) without affecting renal clearance, demonstrating pure metabolic inhibition 4.
No significant interaction occurred in CYP2D6 poor metabolizers, again confirming enzyme-specific inhibition 4.
Clinical Implications for Drug Selection
Tamoxifen Considerations
Avoid diphenhydramine in patients taking tamoxifen when possible, as CYP2D6 inhibition can reduce conversion to the active metabolite endoxifen, though diphenhydramine is not specifically listed among the potent inhibitors (paroxetine, fluoxetine) that guidelines explicitly warn against 5.
The 2024 NCCN guidelines recommend avoiding potent and intermediate CYP2D6 inhibitors in tamoxifen-treated patients, though they focus primarily on SSRIs rather than antihistamines 5.
Other CYP2D6 Substrates
Exercise caution when combining diphenhydramine with narrow therapeutic index CYP2D6 substrates including tricyclic antidepressants, antipsychotics, flecainide, propafenone, and other beta-blockers beyond metoprolol 5, 3.
The inhibitory concentrations of diphenhydramine (2-11 μM) fall within the range of expected hepatic blood concentrations at therapeutic doses, making clinically relevant interactions probable 1.
Genotype-Dependent Effects
CYP2D6 ultrarapid metabolizers (1-2% of the US population) may experience paradoxical excitation on diphenhydramine due to abnormally rapid conversion to potentially excitatory metabolites 6.
The clinical effects of diphenhydramine and its drug interactions are negligible in CYP2D6 poor metabolizers (7-10% of population), as these individuals lack functional enzyme activity 3, 4.
Practical Recommendations
When antihistamine therapy is needed in patients taking CYP2D6 substrates with narrow therapeutic indices, consider second-generation antihistamines (loratadine, cetirizine, fexofenadine) that do not inhibit CYP2D6 5.
Monitor for enhanced drug effects (increased sedation, cardiovascular effects, or other substrate-specific toxicities) when diphenhydramine is combined with CYP2D6 substrates in extensive metabolizers 3, 4.
The inhibitory effect occurs at standard therapeutic doses (50 mg every 12 hours), not just supratherapeutic doses, making this a clinically relevant concern in routine practice 3, 4.
Common Pitfalls
Do not assume diphenhydramine is safe simply because it is available over-the-counter—its CYP2D6 inhibition is comparable to some prescription medications and can cause significant drug interactions 1, 3.
Do not overlook the duration of inhibition, which persists as long as diphenhydramine maintains therapeutic concentrations (4-6 hours per dose) 7.
Do not forget that the interaction is genotype-dependent—patients who are CYP2D6 poor metabolizers will not experience this interaction, while ultrarapid metabolizers may have unexpected responses 6, 3, 4.