Pharmacokinetics of the recombinant thrombolytic agents: what is the clinical significance of their different pharmacokinetic parameters?
In addition to the first generation thrombolytics streptokinase and urokinase there are now a number of new human thrombolytic proteins produced by recombinant techniques. In this review alteplase, saruplase and reteplase are discussed. These compounds differ with respect to their pharmacokinetics. Alteplase and saruplase have relatively short half-lives and are high clearance compounds. Their clearance is dependent upon the hepatic blood flow. This is relevant as myocardial function strongly influences liver blood flow and hence the clearance of alteplase and saruplase. The clearance of reteplase is less dependent upon liver blood flow and is partly dependent on renal excretion. This extends its half-life and reteplase has been successfully administered as a double bolus injection. The question remains if these differences are responsible for any clinical benefits that could not be accomplished by variations in dosage or dosage schedule for a single thrombolytic. Pharmacokinetic differences can only be interpreted if reasonable knowledge exists about the shape and location of the plasma concentration- (adverse) effect curves. This information is not yet available for the recombinant thrombolytic drugs and any clinical differences could well be caused purely by differences in dosage or dosage schedule. It is recommended that plasma concentrations of thrombolytics are measured in future clinical trials, for which techniques are currently available.
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Leiden University Medical Centre, Centre for Human Drug Research, Leiden, The Netherlands. info@chdr.leidenuniv.nl