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Clearance and Tissue Distribution of Recombinant Human Interleukin 1ß in Rats

Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima 771-01, Japan

Clearance and tissue distribution of recombinant human interleukin 1ß (IL-1ß) were investigated by determining the growth-inhibitory activity on tumor cells in rats after i.v. or s.c. administration.

A single 100 µg/kg i.v. bolus was biphasically eliminated with a terminal half-life of 19.0 min in normal rats. Serum IL-1ß 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-1ß activity was mainiy located in the kidney and was particularly accumulated in the lysosomal fraction. A 14-fold increase in the elimination half-life of IL-1ß activity was found in nephrectomized rats, in comparison with shamtreated control rats. Pretreatment with E-64 and leupeptin, both of which are thiol protease inhibitors, had no effect on the plasma levels of IL-1ß activity, but a 2-fold increase in plasma level was found in rats pretreated with pepstatin A, a carboxyl protease inhibitor.

Since excreted IL-1ß 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.

¹ To whom requests for reprints should be addressed.

Received 12/27/89. Accepted 6/15/90.

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