Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US) or cardiac edema (Japan). Tolvaptan absolute bioavailability was determined in a single-center, open-label, sequential administration trial in which intravenous (i.v.) placebo (Day -2), i.v. 1 mg tolvaptan (Day 1) and an oral 30 mg tablet (Day 8) were administered to 14 healthy subjects. Urine volume and osmolality were determined on Days -2, 1 and 8 at multiple intervals postdose; 24-h fluid balance was also assessed. On Days 1 and 8, blood samples for tolvaptan were collected for 48 h postdose. Mean absolute bioavailability was determined to be 56% (range 42 - 80). Mean peak tolvaptan concentration at 1 h (end-of-infusion) was 32.7 (range 18 - 45) ng/ml compared to 231 (range 87 - 410) ng/ml for the oral dose. In the 4-h period from start of the 1 mg tolvaptan i.v. infusion, 12 of 14 subjects experienced increased urine volume and decreased urine osmolality; both parameters were affected for 24 h postdose following the 30 mg oral dose. Minimally effective concentrations are rapidly achieved after oral dosing as all subjects had tolvaptan concentrations > 20 ng/ml at 1 h postdose.