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 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-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 125I-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 125I-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.
Reimers
J
J
Steno Memorial and Hvidøre Hospital, Gentofte, Denmark.
Wogensen
L D
LD
Welinder
B
B
Hejnaes
K R
KR
Poulsen
S S
SS
Nilsson
P
P
Nerup
J
J
D000818:Animals; D001345:Autoradiography; D006207:Half-Life; D007375:Interleukin-1 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008297:Male; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics
D007375:Interleukin-1; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha