The pharmacokinetics and absolute oral bioavailability of zaleplon were assessed to evaluate the extent of presystemic metabolism of this new nonbenzodiazepine hypnotic agent. A partially randomized, single-dose, four-period crossover study was conducted in 23 healthy subjects. Subjects received 1 and 2.5 mg intravenous (i.v.) infusions of zaleplon during the first and second periods, respectively, and then were randomly assigned to receive a 5 mg oral dose or 5 mg i.v. infusion of zaleplon in a crossover design during the final two periods. Zaleplon pharmacokinetics were determined in 20 subjects (ten men and ten women) after the two 5 mg treatments. The oral and i.v. doses of zaleplon administered in this study were safe and well-tolerated. Following i.v. administration, zaleplon had a moderate to high systemic clearance (mean +/- S.D., 0.94 +/- 0.20 L/h/kg), rapid elimination (half-life, t1/2 = 1.05 +/- 0.13 h), and a steady-state volume of distribution of 1.27 +/- 0.25 L/kg, indicating substantial distribution into extravascular tissues. Zaleplon was rapidly absorbed after oral administration, and the mean apparent elimination t1/2 was similar to that obtained after i.v. infusion. The absolute bioavailability was 30.6 +/- 10.2%.