Plasma levels and urinary excretion of diphenhydramine were measured after administration of three single 50-mg doses of diphenhydramine hydrochloride to two healthy male volunteers as an intravenous infusion, an oral solution, and a commercially available capsule. A large first- pass effect was evident from the data, with about 50% of the drug being metabolized by the liver before it reached the general circulation. The drug in solution given orally appeared to be fully available to the hepatoportal system, and the availability of diphenhydramine from the capsule was about 83% relative to the solution in one subject and 100% in the other subject. Cumulative amounts of unchanged diphenhydramine excreted in the urine were less than 4% of the administered dose. Both subjects went to sleep at the end of the 1-hr intravenous infusion, but were only drowsy following the oral treatments.