Studies of recombinant plasminogen activator inhibitor-1 in rabbits. Pharmacokinetics and evidence for reactivation of latent plasminogen activator inhibitor-1 in vivo

D. E. Vaughan, P. J. Declerck, E. Van Houtte, M. De Mol, D. Collen*

*Corresponding author for this work

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The pharmacokinetics of human recombinant plasminogen activator inhibitor-1 (rPAI-1) was studied in rabbits. Latent rPAI-1 (0-2 units of tissue-type plasminogen activator neutralizing activity per microgram protein); reactivated rPAI-1 (approximately 150 units/μg); and chloramine T-oxidized, nonreactivatable rPAI-1 (approximately 0.7 units/μg) were studied. The pharmacokinetic parameters for the disposition of rPAI-1 antigen after an intravenous bolus injection of 1.0 or 2.5 mg/kg rPAI-1 were very similar for all three forms: the initial volume of distribution was approximately 60 ml/kg, the initial half-life in plasma was 6 minutes, and the plasma clearance was approximately 4 ml/kg/min. The disposition of PAI activity after injection of reactivated rPAI-1 was similar to that of rPAI-1 antigen. Injection of latent rPAI-1 was associated with a nearly threefold increase in the specific activity of circulating PAI-1 from 2 units/μg to 5.0 ± 1.1 units/μg (p < 0.01) within 1 minute, followed by a cumulative 25-fold increase in specific activity over 1 hour (p = 0.01). In contrast, the specific activity of oxidized or reactivated preparations of rPAI-1 did not increase in the first several minutes after injection. These findings support the existence of a fast-acting but low-capacity mechanism for the reactivation of rPAI-1 in vivo.

Original languageEnglish (US)
Pages (from-to)1281-1286
Number of pages6
JournalCirculation Research
Volume67
Issue number5
DOIs
StatePublished - Jan 1 1990

Keywords

  • pharmacokinetics
  • plasminogen activator inhibitor-1
  • reactivation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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