Dose-dependent pharmacokinetics of recombinant tissue-type plasminogen activator in anesthetized dogs following intravenous infusion.
The pharmacokinetics of SK&F recombinant two-chain tissue-type plasminogen activator (tPA) following intravenous (iv) 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at rates of 0.5, 1, 2, 4, and 8 micrograms/kg/min (N = 3 to 5 per dose) for 90 min, and arterial blood samples were withdrawn during and after infusion for determination of functionally active tPA concentrations using a modified and validated S-2251 chromogenic assay.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 the dose in the range of 0.5-4 micrograms/kg/min. However, as the dose was increased 2-fold from 4 to 8 micrograms/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 micrograms/kg/min, but decreased to 11.7 ml/min/kg at the 8 micrograms/kg/min dose. With exceptions in three 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 micrograms/kg/min dose. At steady state, active tPA accounted for 40-60% of the total tPA antigen. The postinfusion t1/2 of the tPA antigen was considerably longer (13.46 +/- 5.94 min) than that of active tPA.(ABSTRACT TRUNCATED AT 250 WORDS)
D000758:Anesthesia; D000818:Animals; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D007262:Infusions, Intravenous; D008297:Male; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000096:biosynthesis / Q000493:pharmacokinetics*
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator