Kidney as a major clearance organ for recombinant human interleukin-1 receptor antagonist.
This study was designed to provide information on the tissue distribution and elimination of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in rats. Following intravenous (iv) bolus administration of metabolically labeled [35S]rhIL-1ra alone or together with unlabeled rhIL-1ra, biodistribution of [35S]rhIL-1ra in the early phase as well as at steady state was investigated. The renal elimination of rhIL-1ra at steady state was also studied. In the early phase biodistribution study, 11, 9, 6, and 2% of the dose was distributed to the kidney, liver, gut, and lung, respectively. Additional rhIL-1ra was found in muscle (43%) and plasma (26%). The time profiles of [35S]rhIL-1ra in the kidney and liver were analyzed by integration plots to determine the early-phase distribution clearance of [35S]rhIL-1ra. The distribution clearance of [35]rhIL-1ra per gram of kidney was five times greater than that of the liver. When expressed as clearance per organ, total liver clearance and total renal clearance were comparable, together accounting for approximately 20% of plasma clearance in the early phase. The distribution clearances of [35S]rhIL-1ra in these tissues (liver and kidney) were not affected by coadministration of excess unlabeled rhIL-1ra (5 mg/rat), indicating that clearance occurs via a mechanism having a high capacity for rhIL-1ra. The steady-state biodistribution of rhIL-1ra was also studied to examine the accumulation of rhIL-1ra in the tissues. The tissue-to-plasma concentration ratios at steady state were similar to the corresponding extracellular spaces in the tissues investigated except the kidney, where the ratio was 4.10.(ABSTRACT TRUNCATED AT 250 WORDS)
Kim
D C
DC
Synergen Inc., Boulder, CO 80301-2546, USA.
Reitz
B
B
Carmichael
D F
DF
Bloedow
D C
DC
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D053590:Interleukin 1 Receptor Antagonist Protein; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000493:pharmacokinetics*; D012795:Sialoglycoproteins / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins