The first pass uptake of fentanyl in the human lung was studied in two groups of patients using a double indicator dilution technique. A bolus containing fentanyl and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of fentanyl taken up by the lung during the first pass and the instantaneous extraction of fentanyl at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. In patients who had been receiving no other drugs prior to the experiment, the total first pass uptake (mean +/- SE) of fentanyl was 82.6% +/- 1.4% of the injected dose. In patients who had been receiving 30-120 mg/day of propranolol the total first pass uptake (mean +/- SE) of fentanyl decreased to 52.8% +/- 6.3% of the injected dose. In one patient on 120 mg of propranolol per day, first pass uptake of fentanyl was only 20.3% of the injected dose. Additional studies in a rat isolated perfused lung preparation coperfused with fentanyl and propranolol also demonstrated that one basic lipophilic amine (propranolol) could inhibit the pulmonary uptake of a second basic lipophilic amine (fentanyl). The high first pass uptake of fentanyl in the human lung limits the rate of entry of this drug into the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)