Studies in humans and conscious animals have established that the kidney is a key organ involved in the clearance of the brain-gut peptide neurotensin (NT). However, these in vivo studies cannot determine the mechanisms involved in the renal elimination of NT. We have therefore used the isolated perfused rat kidney preparation, which enables renal elimination to be studied in isolation from other organs. NT was measured with both COOH-terminal (biologically active end) and NH2-terminal (biologically active end) directed antisera. NT was stable in control perfusions (no kidney) with a disappearance half-life of greater than 250 min. The disappearance half-life in filtering kidneys was 52 +/- 3 min (COOH terminal) and 67 +/- 3 min (NH2-terminal). High-performance liquid chromatography of perfusate revealed a pattern similar to that seen in vivo with the NT being metabolized to NH2-terminal fragments. When the kidneys were rendered nonfiltering, NH2-terminal clearance was abolished, whereas COOH-terminal clearance was reduced by 75%. There was no release of NT peptidases into the perfusate. These data demonstrate that NT is metabolized directly by the kidney, predominantly by a filtration and reabsorption mechanism and with only a minor role for peritubular metabolism.