THE PHARMACOKINETICS, DISTRIBUTION AND DEGRADATION OF HUMAN RECOMBINANT INTERLEUKIN 1-BETA IN NORMAL RATS

Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half-lives of distribution (T1/2-alpha) and elimination phases (T1/2-beta) of human recombinant interleukin 1-beta (rIL-1-beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active I-125-rIL-1-beta. After intravenous (i.v.) injection, I-125-rIL-1-beta was eliminated from the circulation with a T1/2-alpha of 2.9 min and a T1/2-beta of 41.1 min. The central and peripheral volume of distribution was 20.7 and 19.1 ml/rat, respectively, and the metabolic clearance rate was 16.9 ml/min/kg. The kidney and liver showed the highest accumulation of tracer, and autoradiography demonstrated that I-125-rIL-1-beta was localized to the proximal tubules in the kidney and to the hepatocytes in the liver. Furthermore, grains were localized to the islets of Langerhans in the pancreas. Tracer-bound proteins corresponding to intact I-125-rIL-1-beta were found in the circulation after i.v., intraperitoneal (i.p.) and subcutaneous (s.c.) injections, as demonstrated by high performance size exclusion chromatography, trichloracetic acid precipitation and SDS-PAGE until 5 h after tracer injection. Pre-treatment with 'cold' rIL-1-beta enhanced degradation of a subsequent injection of tracer. The route of administration was of importance for the biological effects of rIL-1-beta, as demonstrated by a reduced food intake, increased rectal temperature and blood glucose after s.c. injection of rIL-1-beta compared with i.p. The present demonstration of intact rIL-1-beta in the circulation and the islets of Langerhans supports the hypothesis that systemic IL-1-beta may be involved in the initial beta-cell destruction leading to IDDM in humans.