What is the metabolism of Benadryl (diphenhydramine)?

Metabolism of Diphenhydramine (Benadryl)

Diphenhydramine is primarily metabolized in the liver through the cytochrome P450 enzyme system, with CYP2D6 serving as the main enzyme responsible for its N-demethylation, which is the primary metabolic pathway. 1

Primary Metabolic Pathway

• Diphenhydramine undergoes extensive first-pass metabolism in the liver, which is a prerequisite for its excretion 2
• CYP2D6 is the high-affinity enzyme primarily responsible for diphenhydramine N-demethylation with a Km value of 1.12 ± 0.21 μM 1
• Additional cytochrome P450 enzymes involved as low-affinity components include CYP1A2, CYP2C9, and CYP2C19 1
• The metabolism results in the formation of more polar metabolites that can be more easily excreted 2

Pharmacokinetic Properties

• Diphenhydramine is rapidly absorbed from the gastrointestinal tract with good bioavailability 2
• It is distributed quickly throughout the body, including the central nervous system 2
• The onset of action occurs within several minutes after administration 2
• The duration of effect is approximately 4-6 hours 2
• Diphenhydramine has a relatively short half-life compared to other medications like tricyclic antidepressants (which have half-lives of 12-36 hours) 3

Genetic Variations in Metabolism

• Genetic polymorphisms in CYP2D6 can significantly affect diphenhydramine metabolism 1, 4

• Four phenotypes exist based on CYP2D6 activity:

  • Poor metabolizers (PMs): Reduced enzyme activity leading to higher drug concentrations and potential toxicity 2
  • Intermediate metabolizers (IMs): Moderately reduced enzyme activity 2
  • Extensive metabolizers (EMs): Normal enzyme activity 2
  • Ultrarapid metabolizers (UMs): Enhanced enzyme activity, potentially leading to subtherapeutic concentrations or paradoxical effects 2, 4

• CYP2D6 ultrarapid metabolizers (approximately 1-2% of the US population) may experience paradoxical excitation rather than sedation with diphenhydramine 4

Dual Role as Substrate and Inhibitor

• Diphenhydramine is not only a substrate of CYP2D6 but also acts as an inhibitor of this enzyme 1
• This dual role can lead to potential drug interactions when diphenhydramine is co-administered with other medications metabolized by CYP2D6 1, 5
• The inhibitory effect on CYP2D6 may contribute to its sedative properties in normal metabolizers 1

Clinical Implications

• Individual differences in CYP2D6, CYP1A2, CYP2C9, and CYP2C19 activity can cause variations in:

  • Anti-allergic efficacy 1
  • Sedative effects 1
  • Risk of adverse reactions 1, 6

• Drug interactions are possible when diphenhydramine is combined with:

  • Other CYP2D6 substrates or inhibitors 1, 5
  • Central nervous system depressants (including benzodiazepines, opioid narcotics, and alcohol) 2

• Rare but serious adverse effects include drug-induced liver injury, which has been reported even in the absence of concomitant medications 6

Elimination

• After metabolism, diphenhydramine and its metabolites are primarily eliminated through the kidneys 2
• Renal insufficiency may affect the clearance of diphenhydramine and its metabolites, though to a lesser extent than hepatic impairment 2
• Hepatic impairment can significantly impact diphenhydramine metabolism and clearance 2, 6

Understanding the metabolism of diphenhydramine is crucial for predicting its efficacy, potential side effects, and interactions with other medications, particularly in patients with genetic variations in CYP2D6 activity or those with hepatic impairment.