Metabolism of cholecystokinin (CCK) and the effect of L-364,718, a specific CCK-A receptor antagonist, on the metabolism of CCK were examined in dogs. In conscious dogs, 45 min intravenous infusion of synthetic human CCK-33 (100 pmol/Kg/hr) caused an integrated CCK response over 90 min of 675 +/- 51 pmol-90 min/L, and the plasma CCK levels declined promptly with a t1/2 of 2.2 +/- 0.3 min after cessation. Organ extraction of CCK-33 by the kidney, mesenteric organs, and liver was examined in anesthetized dogs. From the gradients of the plasma levels between afferent and efferent vessels for each organ after bolus injection of CCK-33 (50 pmol/Kg), renal extraction ratio was 0.30 +/- 0.04, and mesenteric extraction ratio was 0.19 +/- 0.04. Hepatic extraction was not detected. T1/2 and extraction ratios were not affected by the preinjection of L-364,718 (20 nmol/Kg). The results indicate in dogs that exogenously administered CCK-33 is degraded by the mesenteric organs as well as the kidney but not by the liver, and that receptor-mediated mechanisms are not involved in these degradation pathways of CCK.