Clearance and tissue distribution of recombinant human interleukin 1 beta (IL-1 beta) were investigated by determining the growth-inhibitory activity on tumor cells in rats after i.v. or s.c. administration. A single 100 micrograms/kg i.v. bolus was biphasically eliminated with a terminal half-life of 19.0 min in normal rats. Serum IL-1 beta activity reached a maximum level 1 h after s.c. administration and then declined with a half-life of 1.59 h. The absolute bioavailability was 40.5%. IL-1 beta activity was mainly located in the kidney and was particularly accumulated in the lysosomal fraction. A 14-fold increase in the elimination half-life of IL-1 beta activity was found in nephrectomized rats, in comparison with sham-treated control rats. Pretreatment with E-64 and leupeptin, both of which are thiol protease inhibitors, had no effect on the plasma levels of IL-1 beta activity, but a 2-fold increase in plasma level was found in rats pretreated with pepstatin A, a carboxyl protease inhibitor. Since excreted IL-1 beta activity was not detected in urine, these results suggest that the kidney is the main site of its metabolic degradation and that carboxyl protease is involved in its metabolic inactivation.