Pharmacokinetic Properties of a Novel Tissue-Type Plasminogen Activator Pamiteplase After Single Intravenous Administration to Rats, Dogs, and Monkeys

Abstract

The pharmacokinetics of pamiteplase and recombinant tissue-type plasminogen activator (rt-PA) in rats, dogs, and monkeys were examined using a newly developed enzyme-linked immunosorbent assay (ELISA). Plasma concentrations after intravenous administration of pamiteplase to rats declined in a triphasic manner. Plasma concentrations after intravenous administration of pamiteplase to dogs or monkeys declined in a biphasic manner. The area under the plasma concentration–time curve from zero to infinity (AUC 0→∞) in rats and dogs increased with increasing dose. The half-life and mean residence time of pamiteplase in rats, dogs, and monkeys were shown to be longer than those of rt-PA. Total clearance (CL total) of pamiteplase was only 7–16% that of rt-PAs, suggesting that concentrations of pamiteplase in plasma were higher and more continuous than those of rt-PA in these experimental animals. The data suggest that a bolus administration of pamiteplase shows the same thrombolytic activity as continuous infusion of rt-PA in experimentally induced thrombosis in rats and dogs. The pharmacokinetic parameters distribution volume at the steady state and CL total calculated by immunoreactive concentration after administration of pamiteplase to rats, dogs, and monkeys show high correlation with body weights ( r 2=.7728 and .9039).