title: Effects of changing liver blood flow by exercise and food on kinetics and dynamics of saruplase.
abstract: OBJECTIVE
  To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator.
  
  
  METHODS
  This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, alpha 2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography.
  
  
  RESULTS
  The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: -35%, -19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics.
  
  
  CONCLUSIONS
  u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow.
authors.affiliation: Centre for Human Drug Research, University Hospital Leiden, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: van Griensven
authors.forename: K J
authors.initials: KJ
authors.lastname: Burggraaf
authors.forename: J
authors.initials: J
authors.lastname: Gerloff
authors.forename: W A
authors.initials: WA
authors.lastname: Günzler
authors.forename: H
authors.initials: H
authors.lastname: Beier
authors.forename: R
authors.initials: R
authors.lastname: Kroon
authors.forename: L G
authors.initials: LG
authors.lastname: Huisman
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; D004792:Enzyme Precursors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015444:Exercise / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D005502:Food; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging; D008102:Liver Circulation / Q000502:physiology*; D008297:Male; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D012016:Reference Values; D018617:Ultrasonography, Doppler, Pulsed; D014568:Urokinase-Type Plasminogen Activator / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004792:Enzyme Precursors; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase