Ten healthy male subjects received 25 mg of promethazine intramuscularly, followed within 3 weeks by oral administration of 25 mg. Whole blood and parotid saliva were collected over a 12-hr period after drug administration. Promethazine was quantitated by high-performance liquid chromatography. After intramuscular administration, the promethazine concentrations were 3.0-22.4 ng/ml in blood and 0.9-2.8 ng/ml in parotid saliva. After oral administration, the promethazine concentrations were 1.4-5.5 ng/ml in blood and 0.2-0.8 ng/ml in parotid saliva. The peak blood promethazine concentration after the intramuscular dose was four times higher than that following the oral dose, which indicates that promethazine possesses an extensive first-pass effect. The mean parotid saliva to whole blood ratio (S/B) was calculated to be 0.24 after the intramuscular route an 0.20 after the oral route over the 12-hr period. The calculated percentage of free drug in the blood was 20-24% of the whole blood concentration determined from the S/B ratio.