PHARMACOKINETICS AND PHARMACODYNAMICS OF SARUPLASE, AN UNGLYCOSYLATED SINGLE-CHAIN UROKINASE-TYPE PLASMINOGEN-ACTIVATOR, IN PATIENTS WITH ACUTE MYOCARDIAL-INFARCTION

We examined in patients with acute myocardial infarction (AMI) the pharmacokinetics of saruplase, an unglycosylated, single chain, urokinase-type plasminogen activator (rscu-PA) by measuring urokinase-type plasminogen activator (u-PA) antigen and total u-PA activity, its conversion to active two-chain urokinase-type plasminogen activator (tcu-PA) and evaluated its effect on haemostatic parameters. Twelve patients were studied during and after administration of 20 mg bolus plus 60 mg continuous 1 h i.v. infusion of saruplase. For u-PA antigen and total u-PA activity (expressed as protein equivalents), where 234 U corresponds to 1 mu g, respectively, steady state plasma concentrations were 2.75 +/- 8.3 and 2.50 +/- 7.0 mu g/ml (mean +/- standard deviation) and were reached within 20 min, t(1/2 lambda 1) was 9.1 +/- 1.8 and 7.8 +/- 1.3 min, t(1/2 lambda 2) 1.2 +/- 0.2 and 1.9 +/- 0.5 h, and the total clearance was 393 +/- 110 and 427 +/- 113 ml/min. Inactivation of saruplase in plasma was negligible. After 15 min, tcu-PA was detected in plasma. From the ratio of the areas under the curve of tcu-PA and total u-PA activities it was calculated that 28 +/- 9.3% of the saruplase dose is converted into active Icu-PA. Systemic plasminaemia occurs as shown by a decrease in alpha(2)-antiplasmin and fibrinogen and an increase in fibrinogen degradation products. Thrombin-antithrombin complex formation indicated activation of the clotting system. Saruplase is eliminated rapidly from plasma in AMI patients. A variable, but significant proportion of saruplase is converted into active tcu-PA. At the end of the infusion tcu-PA accounted for 55% of total u-PA activity. Systemic plasmin generation and activation of the clotting system occur during saruplase treatment for AMI.