Tissue-type plasminogen activator precursor tPA t-PA t-plasminogen activator

Mechanism of Action

Alteplase is a recombinant human tissue-type plasminogen activator, a glycoprotein, which activates plasminogen directly to plasmin. When administered intravenously, alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated, inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot.

Pharmacodynamic Properties

Pharmacodynamic effects

Due to its relative fibrin-specificity alteplase at a dose of 100 mg leads to a modest decrease of the circulating fibrinogen levels to about 60% at 4 hours, which is generally reverted to more than 80% after 24 hours. Plasminogen and alpha-2-antiplasmin decrease to about 20 % and 35% respectively after 4 hours and increase again to more than 80% at 24 hours. A marked and prolonged decrease of the circulating fibrinogen level is only seen in few patients.

Pharmacokinetic Properties

Alteplase is cleared rapidly from the circulating blood and metabolised mainly by the liver (plasma clearance 550-680 ml/min). The relevant plasma half-life t1/2 alpha is 4-5 minutes. This means that after 20 minutes less than 10% of the initial value is present in the plasma. For the residual amount remaining in a deep compartment, a beta-half-life of about 40 minutes was measured.

Preclinical Safety Data

In subchronic toxicity studies in rats and marmosets no unexpected undesirable effects were found. No indications of a mutagenic potential were found in mutagenic tests.

In pregnant animals no teratogenic effects were observed after intravenous infusion of pharmacologically effective doses. In rabbits embryotoxicity (embryolethality, growth retardation) was induced by more than 3 mg/kg/day. No effects on peri-postnatal development or on fertility parameters were observed in rats with doses up to 10 mg/kg/day.

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