Summary
Background: The recombinant unglycosylated single chain urokinase-type plasminogen
activator saruplase is cleared for a large part by the liver. A large interindividual
variation in saruplase concentration is found in acute myocardial infarction (AMI)
patients. The variable cardiac performance after an infarct may induce differences
in liver blood flow that could explain the concentration diversity. This study was
performed to investigate the relation between hepatic blood flow and the pharmacokinetic
and pharmacodynamic properties of saruplase.
Methods and Results: Thirteen AMI patients were enroled in this open label study.
Patients received a bolus injection of 20 mg saruplase followed by a one-hour infusion
of 60 mg saruplase. Concurrently 36 mg intravenous indocyanine green (ICG) was given
over 1 h to measure hepatic blood flow. Blood samples were taken at regular time intervals
to measure plasma levels of urokinase-type plasminogen activator (u-PA) antigen and
activity, the two-chain form (tcu-PA) activity, indocyanine green, fibrinogen, fibrin
and fibrin degradation products, α2-antiplasmin and thrombin antithrombin III complex. A correlation was seen between
the clearance of ICG and both those of u-PA antigen (r = 0.62; p <0.05) and u-PA activity
(r = 0.57; p <0.05). A negative correlation was seen between the area under the curve
of tcu-PA activity and the areas under the effect curves of both fibrinogen and α2-antiplas-min (r = -0.84; p <0.01 and r = -0.65; p <0.05).
Conclusions: Liver blood flow is an important determinant of the clearance of u-PA
antigen and activity and reduction of flow in patients with heart failure will lead
to an increase in plasma concentrations. High plasma concentrations of tcu-PA activity
lead to increased systemic fibrinogenolysis. These results may be used to optimize
saruplase treatment in patients with impaired cardiac function or after co-medication
with drugs that affect liver blood flow.
