The purpose of this study was to determine the presence and extent of pulmonary elimination for 5-fluorouracil (FUra). A secondary aim was to characterize the relative importance of the liver, gastrointestinal tract, splanchnic region, and lungs toward the overall elimination of FUra. A total of 10 mixed-breed male and female dogs were used in these acute studies in which FUra was administered through a cephalic vein. Six dogs were studied at sequentially escalated dose rates of 0.125, 0.250, 0.500, 0.750, and 1.00 micromol/min/kg (8-fold range); four dogs were studied at sequentially escalated dose rates of 0.0625, 0.250, 0.750, 1.50, and 2.00 micromol/min/kg (32-fold range). Each infusion lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, and pulmonary artery), perfusion rates were measured (hepatic artery, portal vein, and cardiac output), and pharmacokinetic parameters were directly assessed. Pulmonary elimination of FUra was conclusively demonstrated. Although only 17% of the drug was extracted by the lungs at the lowest dose rate, pulmonary clearance (16.0 ml/min/kg) was on the order of splanchnic clearance (13.5 ml/min/kg), or larger. As the dose rate increased, pulmonary clearance was more easily saturated than splanchnic clearance. Thus, it appears that at increasing dose rates, the splanchnic region becomes a more significant pathway, whereas the lungs have a reduced role in the overall elimination of FUra.