Extrahepatic metabolism of frusemide in anaesthetized rabbits.

1. Frusemide is removed from the body by biotransformation and renal secretion, but since frusemide metabolism is not altered in patients with hepatic cirrhosis, the role of the liver may be questioned. The aim of the study was to investigate which organs contribute to the first-pass metabolism and systemic clearance of frusemide. 2. Groups of anaesthetized New Zealand rabbits were administered frusemide proximally (prox) and distally (dist) to different organs, and blood was sampled from the abdominal aorta. The area under frusemide plasma concentrations-time curve (AUC0-infinity) was calculated and frusemide extraction by an organ was estimated from the ratio (AUCdist-AUCprox)/AUCdist. The small intestine extracted 83% of the absorbed dose of frusemide but the first-pass uptake by the liver and lungs was negligible. 3. To assess the contribution of the intestine and the kidneys to the systemic clearance of frusemide, it was injected into the jugular vein and blood was sampled proximal and distal to each organ. The kidneys extracted 24% of frusemide circulating in the renal arteries; on the other hand, the ability of the intestine to extract frusemide from the systemic circulation could not be detected. 4. The lungs did not metabolize frusemide in vitro; the rate of metabolism of frusemide in vitro by kidneys was similar to that estimated in the intestine, and both rates were faster (P < 0.05) than that observed in the liver. 5. It is concluded that in rabbits, presystemic metabolism of frusemide is carried out by the intestine, and that systemic clearance of frusemide is mainly performed by the kidneys, although other organs, such as the intestine and the liver, must contribute to it.