title: Effects of increased liver blood flow on the kinetics and dynamics of recombinant tissue-type plasminogen activator.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: van Griensven
authors.forename: L G
authors.initials: LG
authors.lastname: Huisman
authors.forename: T
authors.initials: T
authors.lastname: Stuurman
authors.forename: G
authors.initials: G
authors.lastname: Dooijewaard
authors.forename: R
authors.initials: R
authors.lastname: Kroon
authors.forename: R C
authors.initials: RC
authors.lastname: Schoemaker
authors.forename: K
authors.initials: K
authors.lastname: Kluft
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D006801:Humans; D008099:Liver / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D010960:Plasminogen Activators / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D012039:Regional Blood Flow; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D011994:Recombinant Proteins; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator