A comparison of mass balance, pharmacokinetics and disposition of [14C(U)]- and [125I]recombinant human interleukin-2 in cynomolgus monkeys.
Recombinant human interleukin-2 (rHuIL-2) has been metabolically labeled with 14C amino acids in Escherichia coli and affinity purified on a rHuIL-2 receptor affinity column. The radiolabeled molecule had a specific radioactivity of 238 dpm/unit and the identical amino acid sequence and biological activity as unlabeled rHuIL-2. In this study, we used this labeled [14C(U)]rHuIL-2 and commercially available [125I]rHuIL-2 (identical in sequence to the [14C(U)]rHuIL-2) to compare the mass balance, pharmacokinetics, and disposition in cynomolgus monkeys. After a single intravenous bolus dose of 4 x 10(5) units/kg, serum samples were collected for 7 days and examined for biological activity, total radioactivity, and by molecular size exclusion chromatography. Urine and feces were analyzed for total radioactivity. When analyzed for biological activity, both [14C(U)]- and [125I]rHuIL-2 exhibited the following pharmacokinetic parameters: terminal elimination half-life of 1-2 hr, AUC0-infinity ranged from 2005 to 4659 units x hr/ml, clearance was 90-200 ml/hr/kg, and volume of distribution ranged from 103 to 163 ml/kg. Comparison of the pharmacokinetic profiles of the two radiolabels were very different from bioactivity, in that the elimination half-lives for radioactivity were approximately 8 days and 10 hr for [14C(U)]- and [125I]rHuIL-2, respectively. We conclude that the [14C(U)]rHuIL-2 was metabolized to constituent amino acids and recycled into newly synthesized proteins from our size exclusion chromatography studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Nadeau
R W
RW
Department of Drug Metabolism 86/726, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA.
Satoh
H
H
Scheide
S
S
Crowl
R
R
Conroy
R
R
Garland
W A
WA
Liberato
D J
DJ
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002850:Chromatography, Gel; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D007376:Interleukin-2 / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D013601:T-Lymphocytes / Q000378:metabolism; D014018:Tissue Distribution
D000596:Amino Acids; D002250:Carbon Radioisotopes; D007376:Interleukin-2; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins