The kinetics and psychomotor effects of diphenhydramine were investigated in Orientals and Caucasians. Each of 5 Oriental and 5 Caucasian young adults received on 1 of 3 occasions diphenhydramine 50 mg/70 kg body weight either intravenously or orally, or placebo. Plasma levels of diphenhydramine were measured hourly for 8 hr at each session. Tests of subjective sedation and psychomotor performance were performed at hourly intervals. The results showed that after both intravenous and oral diphenhydramine, at all times Orientals had plasma levels approximately half those of Caucasians. With the assumption of linear kinetics and a 1-compartment open model, analysis of the data showed that the volume of distribution (VD) and plasma clearance (Cl) but not plasma half-life (t 1/2) were higher in Orientals than Caucasians: [VD = 480 +/- 24 (SEM) and 292 +/- 36 1/70 kg; Cl = 79 +/- 7 and 51 +/- 7 1/70 kg/hr; t 1/2 = 4.1 +/- 0.4 and 4.3 +/- 0.4 hr]. Unbound diphenhydramine in fresh plasma was higher in Orientals than Caucasians [24.0 +/- 1.9% (SEM) and 14.8 +/- 1.5%] and probably explains the increased VD in Orientals. Orientals had significantly less sedation and deterioration in psychomotor performance.