Summary.Technosphere/Insulin (TI) is a formulation of regular human insulin and Technosphere, a new drug delivery system for pulmonary administration. The formulation is designed for efficient transport of insulin across the intact respiratory epithelium into the systemic circulation. We have investigated the pharmacodynamic and pharmacokinetic properties of Technosphere/Insulin in five healthy, non-smoking volunteers. In an open, randomized, three-way crossover study, subjects received 5 IU regular human insulin (HI) intravenously, 10 IU HI subcutaneously; and 100 IU TI via inhalation using a small commercially available asthma inhaler. The time action profiles of all three insulin formulations were assessed by the euglycemic glucose clamp technique on three different study days. Glucose infusion rates were monitored from 2 h before until 6 h after insulin administration. Other study measures were serum insulin, serum C-peptide concentrations, and safety parameters. The inhalation of TI was well tolerated. The time to peak action was significantly shorter with both i.v. injection and inhalation, as compared to s.c. (14 +/- 6 min and 39 +/- 36 min vs. 163 +/- 25 min; p < 0.0002 and p < 0.007 (mean +/- SD)). The metabolic effect during the first 3 h after insulin administration was higher with inhaled TI than with HI s.c. (AUC0-180 for glucose infusion rate: 1.94 +/- 0.77 mg/kg * min vs. 1.15 +/- 0.50 mg/kg * min; p < 0.04). Relative and absolute bioavailability for the first 3 h were 26 +/- 12% and 15 +/- 5% respectively (6 h: 16 +/- 8 and 16 +/- 6%). We conclude that inhalation of TI leads to a rapid onset of metabolic action resembling the effect observed with i.v. administration of regular HI. Despite the use of a common asthma inhaler, bioavailability over the three hour prandial period was substantially greater than with other reported pulmonary systems. Therefore, inhalation of Technosphere/Insulin may become a suitable and attractive alternative for prandial insulin delivery, especially for patients with type 2 diabetes mellitus.