EFFECTS OF INCREASED LIVER BLOOD-FLOW ON THE KINETICS AND DYNAMICS OFRECOMBINANT TISSUE-TYPE PLASMINOGEN-ACTIVATOR

Objective: To investigate the influence of increased liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue-typ e plasminogen activator (rt-PA) and to study the changes in endogenous urokinase-type plasminogen activator (u-PA). Methods: This open, rand omized, crossover trial was carried out in a clinical research unit. E ight healthy, nonsmoking volunteers received linear infusions of 24 mg rt-PA and 92 mg indocyanine green over 160 minutes. Sixty minutes aft er the infusions were started, the subjects consumed a standardized me al to increase liver blood flow on one occasion and abstained from tak ing food on the other occasion. Plasma concentrations of indocyanine g reen, tissue-type plasminogen activator (t-PA) antigen, t-PA activity, total u-PA antigen, plasmin-activatable single-chain u-PA (scu-PA), a ctive two-chain u-PA (tcu-PA), fibrinogen, total fibrin, and fibrinoge n/fibrin degradation products (TDP), and alpha(2)-antiplasmin were mea sured. Results: After the consumption of the meal, the area under the curve (AUG) was 35% (95% confidence interval [CI]: 25%, 43%) Ion er fo r 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 subje cts abstained from food. No changes were observed in fibrinogen, TDP, or alpha(2)-antiplasmin concentrations that were attributable to the i ntake 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 c oncentrations by more than 50%. Conclusions: Increased liver blood how results in an increase in t-PA clearance. The conversion of the inact ive zymogen scu-PA to the active tcu-PA is increased by an infusion of rt-PA, but total u-PA antigen concentrations remain unchanged.