Studies of Recombinant Plasminogen Activator Inhibitor-1 in Rabbits: Pharmacokinetics and Evidence for Reactivation of Latent Plasminogen Activator Inhibitor-1 In Vivo

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 formsthe 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/pg to 5.0±1.1 units/μg (p