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Maximum plasma levels of diphenhydramine in normal sub;ects ranged from 81 to 159 ng/ml in 2 to 4 hr after single 100 mg oral doses, with an estimated half-life of 7 hr. Multiple oral doses of 50 mg four times daily for 3 days produced mean peak levels of approximately 110 ng/ml by the second day, with an estimated half-life of 6 ~r. Total amine levels were 50% to 100% higher, due to the presence of N-dealkylated metabolites. Single 100 mg oral doses of diphenhydramine also produced a progressive increase in the plasma levels of acidic metabolites over a 24 hr period, reaching values 10 times those of the maximum diphenhydramine levels. Urinary excretion of total diphenhydramine metabolites represented about 64% of the dose in single dose studies, and 49% after multiple doses. These observations are consistent with earlier studies on the metabolic disposition of labeled diphenhydramine in laboratory animals.

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