The pharmacokinetics of plasminogen activator inhibitor-1 in the rabbit.
The pharmacokinetics of the activated and latent forms of plasminogen activator inhibitor-1 (PAI-1) isolated from HT1080 fibrosarcoma cells (HT1080 PAI-1) and a nonglycosylated form of human PAI-1 isolated from a yeast expression system (rPAI-1) were followed in the rabbit. As assessed by an immunologic assay specific for human PAI-1, guanidine HCI activated HT1080 PAI-1 and rPAI-1 entered the total plasma volume following intravenous bolus administration and exhibited a biphasic clearance pattern. The t1/2s of HT1080 PAI-1 for the initial and beta phases equalled 6.0 and 24.8 minutes, respectively. The t1/2s of rPAI-1 for the initial and beta phases equalled 8.8 and 34.0 minutes, respectively. Similar results were obtained by measuring PAI-1 activity in plasma and with trace amounts of 125I-rPAI-1, suggesting that the above pharmacokinetic behavior could also apply to endogenous PAI-1. The liver was the main site of rPAI-1 clearance. Unactivated, latent PAI-1 exhibited a very different pharmacokinetic profile. Over 80% of latent rPAI-1 cleared from the circulation within 10 minutes (t1/2 = 1.7 minutes). The difference in clearance behavior between activated and latent PAI-1 may be related to the ability of activated PAI-1, but not latent PAI-1, to rapidly form high-molecular-weight complexes with plasma binding factors which were observed in vitro and in vivo. Because PAI-1 could potentially tilt the fibrinolytic balance toward a prothrombotic state, its rapid clearance may represent an important control mechanism governing the circulating levels of this key component of the fibrinolytic pathway.
Mayer
E J
EJ
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
Fujita
T
T
Gardell
S J
SJ
Shebuski
R J
RJ
Reilly
C F
CF
D000818:Animals; D005354:Fibrosarcoma / Q000378:metabolism; D006031:Glycosylation; D019791:Guanidine; D006146:Guanidines / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D015849:Plasminogen Inactivators / Q000097:blood / Q000493:pharmacokinetics*; D011817:Rabbits; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D006146:Guanidines; D015849:Plasminogen Inactivators; D019791:Guanidine