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Altered pharmacokinetics of recombinant human deoxyribonuclease in rats due to the presence of a binding protein.

Authors
  • Mohler, M
  • Cook, J
  • Lewis, D
  • Moore, J
  • Sinicropi, D
  • Championsmith, A
  • Ferraiolo, B
  • Mordenti, J
Type
Published Article
Journal
Drug metabolism and disposition: the biological fate of chemicals
Publication Date
Jan 01, 1993
Volume
21
Issue
1
Pages
71–75
Identifiers
PMID: 8095230
Source
Medline
License
Unknown

Abstract

Preclinical pharmacokinetic studies with recombinant human DNase (rhDNase) following a single intravenous injection of 0.01, 0.1, or 1.0 mg/kg in male rats demonstrated that clearance and steady-state volume of distribution increased at the 1.0 mg/kg dose, whereas the mean exit time from the serum remained unchanged. To characterize the molecular form of 125I-rhDNase in serum, rats were intravenously injected with approximately 300 microCi (5 micrograms)/kg 125I-rhDNase or approximately 300 microCi (5 micrograms)/kg 125I-rhDNase with 1 mg/kg unlabeled rhDNase, and blood samples were taken at 2 min. Urine was collected from one rat in each group from 0-6 and 6-24 hr after injection. Serum samples were analyzed by trichloroacetic acid precipitation and native PAGE; urine samples were analyzed by size exclusion HPLC. Native PAGE results indicate that there is a protein present in the serum that binds rhDNase specifically. The presence of excess unlabeled rhDNase decreases the 125I-rhDNase-binding protein complex level relative to free 125I-rhDNase. In contrast, a high-molecular weight peak of radioactivity was seen after size exclusion HPLC of the urine from the animal that received 125I-rhDNase with unlabeled rhDNase rather than the animal that received 125I-rhDNase alone. In addition to its effects on disposition, a specific serum binding protein for rhDNase may play a role in modulating the bioactivity of circulating rhDNase.

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