title: Pharmacokinetics and pharmacodynamics of saruplase, an unglycosylated single-chain urokinase-type plasminogen activator, in patients with acute myocardial infarction.
abstract: 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 microgram, respectively, steady state plasma concentrations were 2.75 +/- 8.3 and 2.50 +/- 7.0 micrograms/ml (mean +/- standard deviation) and were reached within 20 min, t1/2 lambda 1 was 9.1 +/- 1.8 and 7.8 +/- 1.3 min, t1/2 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 tcu-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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: R W
authors.initials: RW
authors.lastname: Koster
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
authors.forename: G R
authors.initials: GR
authors.lastname: Hopkins
authors.forename: H
authors.initials: H
authors.lastname: Beier
authors.forename: W A
authors.initials: WA
authors.lastname: Günzler
authors.forename: P A
authors.initials: PA
authors.lastname: van der Wouw
mesh_terms: D000328:Adult; D000368:Aged; D000990:Antithrombin III / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D006031:Glycosylation; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy*; D010447:Peptide Hydrolases / Q000378:metabolism; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000979:alpha-2-Antiplasmin / Q000378:metabolism
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D005340:Fibrinogen; D010447:Peptide Hydrolases; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase