Effects of increased liver blood flow on the kinetics and dynamics of recombinant tissue-type plasminogen activator

• Published in: Clinical pharmacology and therapeutics Vol. 60; no. 5; p. 504
• Main Authors: van Griensven, J M, Huisman, L G, Stuurman, T, Dooijewaard, G, Kroon, R, Schoemaker, R C, Kluft, K, Cohen, A F
• Format: Journal Article
• Language: English
• Published: United States 01.11.1996
• Subjects: Adult; Cross-Over Studies; Humans; Liver - blood supply; Liver - metabolism; Male; Plasminogen Activators - administration & dosage; Plasminogen Activators - pharmacokinetics; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacokinetics; Regional Blood Flow; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - pharmacokinetics
• ISSN: 0009-9236
• DOI: 10.1016/S0009-9236(96)90146-0

To investigate the influence of increased liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue-type plasminogen activator (rt-PA) and to study the changes in endogenous urokinase-type plasminogen activator (u-PA). This open, randomized, crossover trial was carried out in a clinical research unit. Eight healthy, nonsmoking volunteers received linear infusions of 24 mg rt-PA and 92 mg indocyanine green over 160 minutes. Sixty minutes after the infusions were started, the subjects consumed a standardized meal to increase liver blood flow on one occasion and abstained from taking food on the other occasion. Plasma concentrations of indocyanine green, tissue-type plasminogen activator (t-PA) antigen, t-PA activity, total u-PA antigen, plasmin-activatable single-chain u-PA (scu-PA), active two-chain u-PA (tcu-PA), fibrinogen, total fibrin, and fibrinogen/fibrin degradation products (TDP), and alpha 2-antiplasmin were measured. After the consumption of the meal, the area under the curve (AUC) was 35% (95% confidence interval [CI]: 25%, 43%) lower for indocyanine green, 15% (CI: 6%, 24%) lower for t-PA antigen, and 11% (CI: 2%, 19%) lower for t-PA activity compared to the AUC after subjects abstained from food. No changes were observed in fibrinogen, TDP, or alpha 2-antiplasmin concentrations that were attributable to the intake of food. The infusion of rt-PA caused a fivefold increase in the concentration of active tcu-PA and a concomitant decrease in scu-PA concentrations by more than 50%. Increased liver blood flow results in an increase in t-PA clearance. The conversion of the inactive zymogen scu-PA to the active tcu-PA is increased by an infusion of rt-PA, but total u-PA antigen concentrations remain unchanged.