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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Mast, AE; Salvesen, G; Schnebli, HP; Pizzo, SV

Published Date

  • July 1990

Published In

Volume / Issue

  • 116 / 1

Start / End Page

  • 58 - 65

PubMed ID

  • 2376698

International Standard Serial Number (ISSN)

  • 0022-2143


  • eng

Conference Location

  • United States