DOSE-DEPENDENT PHARMACOKINETICS OF RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR (tPA) IN ANESTHETIZED DOGS FOLLOWING INTRAVENOUS INFUSION

The pharmacokinetics of SK&F recombinant two-cha1n tissue-type plasminogen activator (tPA) following Intravenous (i.v.) infusion were characterized in anesthetized, open chested mongrel dogs in which artificial Intracoronary thrombi were formed. SK&F tPA was Infused at rates of 0.5, 1, 2, 4, and 8 μg/kg/min (n=3 to 5 per dose) for 90 min and arterial blood samples were withdrawn during and after Infusion for determination of functionally active tPA concentrations using a modified and validated S-2251 chromogenlc assay. At all doses studied, steady state active tPA plasma concentrations were achieved 10-20 min after the onset of Infusion. Upon cessation of Infusion, active tPA plasma concentrations declined rapidly with a t1/2 of 2-3 min. The active tPA plasma concentration at steady state (Css) and the area under the tPA plasma concentration-time curve (AUC) Increased linearly with dose in the range of 0.5-4 μg/kg/min. However, as the dose was Increased 2-fold from 4 to 8 μg/kg/min, the AUC and the Css Increased 2.5 fold. The systemic clearance ranged from 15-16 ml/min/kg at doses of 0.5-4 μg/kg/min but decreased to 11.7 ml/min/kg at the 8 μg/kg/min dose. With exceptions in 3 dogs, the volume of distribution at steady state approached or slightly exceeded the blood volume. Plasma tPA antigen concentrations were also determined in the dogs receiving the 2 μg/kg/min dose. At steady state, active tPA accounted for 40-60% of the total tPA antigen. The post-infusion t1/2 of the tPA antigen was considerably longer (13.46 ± 5.94 min) than that of active tPA. These results suggested that non-plasminogen activating metabolites (e.g., tPA-inhlbltor complex(es)) are present in the plasma of dogs receiving tPA. It 1s also concluded from the present study that (1) distribution of the i.v. administered tPA molecule was limited primarily to the Intravascular space, and (2) tPA may display dose-dependent pharmacokinetics within the optimum thrombolytic dose range.