This study was performed to investigate the distribution and the degradation of IV administered [125I]rat epidermal growth factor (rEGF) in the liver and gastrointestinal tract of suckling rats. The bile duct of anesthetized rats was cannulated, and [125I]rEGF was injected (with or without 2500-fold excess unlabeled rEGF) into the femoral vein. After 5, 30, 60, and 120 minutes, the radioactivity in the liver, stomach, small intestine, blood, kidney, bile, and luminal contents of the stomach and small intestine was measured. The extracted radioactivity was then analyzed by immunoaffinity chromatography and binding to EGF-specific receptors. High levels of radioactivity were found in the liver (57% of total administered) and small intestine (10%) at 5 minutes, which gradually decreased. On the contrary, radioactivity secreted in the bile and luminal contents of the small intestine increased with time. The radioactivity in the bile represented 2.4% and 4.5% of the total administered at 60 and 120 minutes, respectively. During the first 60 minutes, more than 90% of the radioactivity in the liver, small intestine, bile, and intestinal contents was immunoreactive. Thirty-four to seventy percent of the radio-activity in the bile and liver and 20%-41% of radioactivity in the small intestinal wall and contents were capable of binding to EGF-specific receptors. Radioactivity detected in the liver, bile, small intestine, and intestinal contents was profoundly reduced by the coinjection excess of unlabeled EGF. These studies show that IV administered [125I]rEGF is rapidly taken up by the liver and the gastrointestinal tract and secreted into the bile and intestinal luminal contents of suckling rats in form(s) capable of binding to anti-EGF antibody and EGF-specific receptors. The uptake and secretion by the liver and the small intestine appear to be receptor mediated.