PMID: 2120422Oct 1, 1990Paper

Nonlinear pharmacokinetics of tissue-type plasminogen activator in three animal species and isolated perfused rat liver

The Journal of Pharmacology and Experimental Therapeutics
P TanswellJ Krause

Abstract

Tissue-type plasminogen activator (t-PA) is cleared rapidly from the circulation via hepatic catabolism, but the capacity of this process is unknown. In this study, increasing doses of human t-PA were administered to rats, rabbits and marmoset monkeys, and in an isolated perfused rat liver system. t-PA concentrations in plasma and perfusate were analyzed pharmacokinetically using procedures in which nonlinear multicompartment models with Michaelis-Menten elimination were fitted to data sets from all doses simultaneously for each species. Elimination of t-PA was saturable, with Km = 12-15 micrograms/ml and Vmax = 200-350 micrograms/ml/hr in vivo. In isolated rat liver, t-PA elimination capacity was considerably reduced, with Km = 1.5 micrograms/ml and Vmax = 3.7 micrograms/ml/hr. At nonsaturating doses, plasma clearance in vivo was 18-23 ml/min/kg and the dominant half-life was 1.1-2.4 min, compared with 8 ml/min/kg and 4.4 min, respectively, in humans; rat liver perfusate clearance was 0.29 ml/min/g. It is concluded that disposition kinetics of t-PA are very similar across species, extrahepatic clearance may be significant in vivo and clearance capacity becomes limited only at plasma concentrations far in excess of clinical the...Continue Reading

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