The hemodynamic basis of reported urethane anesthesia-induced reductions in the clearance of some renally eliminated compounds has been investigated in the laboratory rat. The use of urethane as an anesthetic in pharmacokinetic studies still persists, particularly in experiments of long duration. Using a microsphere technique, the per cent distribution of cardiac output to the kidneys, in both ip urethane- and ip Hypnorm/Hypnovel-anesthetized animals was significantly (p less than 0.01) lower than that observed in ip pentobarbital-anesthetized animals. However, the cardiac index in the Hypnorm/Hypnovel-anesthetized animals was 42% greater (p less than 0.01) than in the pentobarbital-treated animals and 86% greater (p less than 0.01) than in the urethane-treated group. Additionally, the cardiac index in the pentobarbital-anesthetized animals was significantly greater (p less than 0.01) than in the urethane-anesthetized animals. The lower cardiac index and reduced cardiac distribution to the kidneys in the urethane-treated group resulted in significant (p less than 0.01) reductions of approximately 40% in renal blood flow and glomerular filtration rate compared with the animals anesthetized with pentobarbital or Hypnorm/Hypnovel. The transport capacity of the basolateral organic anion secretory mechanism was not compromised by an ip injection of urethane, as demonstrated by p-aminohippuric acid transport studies conducted in isolated renal tubule fragments prepared from anesthetized animals. In conclusion, urethane anesthesia results in significant alterations of renal hemodynamics compared with pentobarbital and Hypnorm/Hypnovel anesthesia in the rat. For primarily renally eliminated compounds, such alterations are likely to influence pharmacokinetic data generated using this anesthetic agent.