Features of urokinase pharmacokinetics at subtherapeutic doses

Objective. To demonstrate potential consequences of miniplasmin-based thrombolysis of highly cross-linked (old) peripheral clots whose dissolution can require repeated administration of thrombolytic agent. Material and methods. Assessment of serum urokinase activity was based on amidolytic activity on urokinase-specific low-molecular-weight substrate S2444. Specific activity of urokinase on this substrate corresponds to cleavage of 12 moles of substrate per second by 1 mole of enzyme. Results. In rabbits not exposed to high plasmin concentrations, urokinase inactivation rate was virtually independent of urokinase dose. In rabbits exposed to plasmin therapy, urokinase inactivation rate increased almost linearly with decreasing baseline urokinase concentration. At a therapeutic dose of urokinase, these rates were comparable in both groups of rabbits. Conclusion. A two-week toxicokinetic experiment with daily 10-fold therapeutic dose of miniplasmin significantly altered pharmacokinetics of urokinase at subtherapeutic doses in six weeks after completion of plasmin therapy.