Clearance of t-PA, PAI-1, and t-PA-PAI-1 complex in an isolated perfused rat liver system.

The role of physiologic inhibitors of tissue-type plasminogen activator (t-PA) in its clearance has not yet been defined. In this study, the clearance of t-PA, plasminogen activator inhibitor 1 (PAI-1), and t-PA-PAI-1 complex was determined in an isolated perfused rat liver system. The clearance of t-PA-PAI-1 complex was twice as fast as that of t-PA, whereas PAI-1 was cleared slowly. The half-lives for t-PA, determined by a two-compartmental pharmacokinetic model, were: alpha, 20.1 minutes, and beta, 120.0 minutes. The corresponding values for t-PA-PAI-1 complex were: alpha, 9.7 minutes, and beta, about 7 hours. The model microconstants were computed for t-PA and t-PA-PAI-1 complex and the marked difference between the "on" microconstants k12 for t-PA (0.026 +/- 0.001 min-1) and t-PA-PAI-1 complex (0.090 +/- 0.025 min-1) suggests that the effect on binding to liver cells is the most important factor in the faster clearance of t-PA-PAI-1 complex when compared with t-PA.