Metabolism and Pharmacokinetics of Diphenhydramine

Primary Metabolic Pathway

Diphenhydramine undergoes extensive first-pass metabolism in the liver, which is a prerequisite for its excretion, resulting in the formation of more polar metabolites that can be more easily excreted 1

Diphenhydramine is rapidly absorbed from the gastrointestinal tract with good bioavailability, distributed quickly throughout the body, including the central nervous system, with an onset of action within several minutes after administration, and a duration of effect of approximately 4-6 hours 2, 3
The American Gastroenterological Association notes that diphenhydramine has a relatively short half-life compared to other medications like tricyclic antidepressants 4

Genetic polymorphisms in CYP2D6 can significantly affect diphenhydramine metabolism, with four phenotypes existing based on CYP2D6 activity: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers, which can lead to variations in drug concentrations and potential toxicity 1

After metabolism, diphenhydramine and its metabolites are primarily eliminated through the kidneys, with renal insufficiency potentially affecting clearance, though to a lesser extent than hepatic impairment, as noted by the European Society of Cardiology 5