Correlation between plasma diphenhydramine level and sedative and antihistamine effects

The sedative and antihistamine effects of diphenhydramine were assessed in relation to plasma concentration after placebo, diphenhydramine 50 mg intravenously, and diphenhydramine 50 mg orally to each of 6 healthy volunteers on three separate occasions. Diphenhydramine plasma elimination t1/2 was 3.0 to 4.3 hr, volume of distribution was 188 to 336 L, and clearance was 637 to 1,014 ml/min. Systemic bioavailability of the oral preparation ranged from 0.26 to 0.60. The sedative effect of intravenous diphenhydramine differed from that of placebo only during the first 3 hr. Antihistamine effect, as measured by reduction of histamine provoked skin wheal diameter, was significantly different from that of placebo for at least 8 hr. There was a positive correlation between plasma diphenhydramine level and sedative and antihistamine effects, but wide variation in the extent and rate of change of these effects were observed between the subject. There appears to be a concentration range of 25 to 50 ng/ml, within which there is significant antihistamine effect without significant sedation.