Drug interactions with thrombolytic agents. Current perspectives.

Thrombolytic agents are widely used for the treatment of acute thromboembolic diseases, especially acute myocardial infarction (AMI). These compounds include streptokinase, anistreplase, alteplase, urokinase and, although not commercially available yet, saruplase (prourokinase). The therapeutic window of these compounds is relatively small and subtherapeutic or toxic plasma concentrations may have serious clinical implications (insufficient thrombolysis, reocclusion and bleeding). Among the factors that affect the pharmacokinetics and pharmacodynamics of thrombolytic agents, comedication is especially relevant since these drug interactions are partly predictable and sometimes preventable. Based on knowledge of the pharmacology of thrombolytic agents and general mechanisms by which pharmacokinetic drug interactions occur, interactions with alteplase and saruplase are expected. The clearance of alteplase is dependent on hepatic blood flow (HBF), and scientific evidence is emerging that saruplase is also a high-clearance compound. Each pharmacological agent that alters HBF and is given concurrently with one of these agents can change the plasma concentrations of those thrombolytics. Although there are no published data confirming drug-induced changes in the metabolism of alteplase or saruplase by this mechanism in humans, indirect supportive evidence (clinical observations and animal experiments) is available. An overview is presented of the anticipated effects of compounds that are frequently coadministered with thrombolytic agents on the pharmacokinetics of the thrombolytics with high-clearance properties. Since the clearance of these thrombolytics may be strongly affected by hypoperfusion of the liver as a result of cardiogenic haemodynamic failure, the role of circulatory changes in potential drug-drug interactions is also discussed. Pharmacodynamic drug interactions are highly relevant in the treatment of acute thrombotic lesions and are still being evaluated to further optimise treatment strategies. As most of these treatments exist as combinations of thrombolytic, antithrombin and antiplatelet compounds, beneficial effects are partly offset by bleeding complications. Changes in the pharmacokinetics and/or pharmacodynamics of thrombolytic agents may have serious consequences. It becomes imperative for the practising physician to be aware of benefits and risks of interactions with thrombolytic agents and especially of the fact that the principal way by which the pharmacokinetics of alteplase and, presumably, saruplase can be affected is by drug- and/or haemodynamic failure-induced changes of HBF.