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Evaluation of the rapid plasma elimination of recombinant alpha 1-proteinase inhibitor: synthesis of polyethylene glycol conjugates with improved therapeutic potential.

Publication ,  Journal Article
Mast, AE; Salvesen, G; Schnebli, HP; Pizzo, SV
Published in: J Lab Clin Med
July 1990

Plasma-derived alpha 1-proteinase inhibitor (alpha 1PlI) is used for replacement therapy in patients with emphysema who have a deficiency of the protein. Future therapy with alpha 1PI with reactive site mutants of this inhibitor will probably require the use of recombinant-derived alpha 1PI (r alpha 1PI). However, the pharmacologic efficacy of r alpha 1PI in humans has been hindered, since r alpha 1PI is rapidly cleared from the circulation of experimental animals. Our studies of the metabolism of r alpha 1PI in mice demonstrate that the rapid clearance of r alpha 1PI is due to renal filtration. However, after preventing renal filtration by ligation of the renal arteries, we find that r alpha 1PI is metabolized in a manner similar to alpha 1PI. Conjugation of r alpha 1PI to polyethylene glycol of Mr approximately 4000 (PEG-4) greatly slows the clearance of r alpha 1PI. The PEG-4 r alpha 1PI conjugate is metabolized in a manner similar to alpha 1PI and has similar kinetic properties before and after oxidation with N-chlorosuccinimide. Moreover, proteinase complexes of PEG-4-r alpha 1PI are catabolized by the same hepatocyte receptor that binds alpha 1PI-proteinase complexes. The results of these studies lay the groundwork for the synthesis of pharmacologically effective r alpha 1PI derivatives with acceptable plasma retention times.

Duke Scholars

Published In

J Lab Clin Med

ISSN

0022-2143

Publication Date

July 1990

Volume

116

Issue

1

Start / End Page

58 / 65

Location

United States

Related Subject Headings

  • alpha 1-Antitrypsin
  • Recombinant Proteins
  • Polyethylene Glycols
  • Pancreatic Elastase
  • Neutrophils
  • Mice
  • Humans
  • General Clinical Medicine
  • Animals
  • 3202 Clinical sciences
 
Journal cover image

Published In

J Lab Clin Med

ISSN

0022-2143

Publication Date

July 1990

Volume

116

Issue

1

Start / End Page

58 / 65

Location

United States

Related Subject Headings

  • alpha 1-Antitrypsin
  • Recombinant Proteins
  • Polyethylene Glycols
  • Pancreatic Elastase
  • Neutrophils
  • Mice
  • Humans
  • General Clinical Medicine
  • Animals
  • 3202 Clinical sciences