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.
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
E J
EJ
Mayer
T
T
Fujita
S J
SJ
Gardell
R J
RJ
Shebuski
C F
CF
Reilly
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