A kinetic analysis of fibrinogenolysis during plasminogen activator therapy.
A mathematic model of the systemic fibrinogenolysis that accompanies coronary thrombolysis with recombinant tissue plasminogen activator (rt-PA) has been devised. The kinetic parameters of the model were estimated by nonlinear regression analysis with data from a clinical trial of rt-PA. The plasma elimination rate constant for rt-PA was estimated to be 10.0 hr-1, the second-order catalytic rate constant for the in vivo rt-PA-mediated conversion of plasminogen to plasmin 0.0078 (microgram rt-PA/kg body weight)-1 hr-1, the plasma elimination rate constant for plasmin 2.33 hr-1, and the second-order catalytic rate constant for the in vivo plasmin-catalyzed degradation of fibrinogen 0.466 (mg plasmin/dl)-1 hr-1. Computer simulation studies based on these parameter estimates show that the magnitude of fibrinogenolysis induced by rt-PA is related to the dose in a curvilinear fashion, showing diminishing increments in the effect at increasing doses. The degree of fibrinogenolysis induced by rt-PA administration is nearly independent of the dosing schedule.
D002986:Clinical Trials as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005340:Fibrinogen / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D008954:Models, Biological; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy; D010958:Plasminogen / Q000378:metabolism; D011446:Prospective Studies; D011897:Random Allocation; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects*
D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator