125I-Labeled rat tonin was injected iv into male Wistar rats weighing 303 +/- 17 g (mean +/- SE), and the disappearance from the circulation, plasma interaction, tissue uptake, and metabolism of radioactivity was studied. After injection, 125I-labeled tonin was immediately bound by alpha 1-macroglobulin, the major circulating protease inhibitor of rats, and the complex was cleared in a biexponential manner: t1/2 of the fast component = 1.8 +2- 0.1 min; t1/2 of the slow component = 84 +/- 10 min; MCR = 2.1 +/- 0.2 ml/min (mean +/- SE, n = 8). The complex was taken up intact by tissues, the major ones being the liver, spleen, adrenal, thyroid, and kidney. Analysis of tissue extracts by gel filtration on Sephadex G-100 showed that the kidney was the major site of metabolism, and radioactivity similar in size to 125I appeared rapidly in urine. Therefore tonin circulates wholly as a complex with alpha 1-macroglobulin (the rat equivalent of human alpha 2-macroglobulin), which once formed is quickly eliminated from the bloodstream by tissue uptake and metabolized.