The Pharmacokinetics, Distribution and Degradation of Human Recombinant Interleukin 1β in Normal Rats

Based upon in vivo rat experiments it was recently suggested that interleukin I in the circulation may be implicated in the initial events of β‐cell destruction leading to insulin‐dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half‐lives of distribution and elimination phases (T1/2β) of human recombinant interleukin 1β(rIL‐1β), and its tissue distribution and cellular localization by means of mono‐labelled, biologically active 125I‐rIL‐1β. After intravenous (iv.) injection, 125I‐rIL‐1β was eliminated from the circulation with a T1/2α of 2.9 min and a T1/2β 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 125I‐rIL‐1β was localized 10 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 125I‐rIL‐1β 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 5h after tracer injection. Pre‐treatment with “cold” rIL‐1β enhanced degradation of a subsequent injection of tracer. The route of administration was of importance for the biological effects of rIL‐1β as demonstrated by a reduced food intake, increased rectal temperature and blood glucose after s.c. injection of rIL‐1β compared with i.p. The present demonstration of intact rIL‐1β in the circulation and the islets of Langerhans supports the hypothesis that systemic IL‐1β may be involved in the initial 1β‐cell destruction leading to IDDM in humans.