Nonlinear pharmacokinetics of tissue-type plasminogen activator in three animal species and isolated perfused rat liver.
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 therapeutic values. Nonlinearity is, however, of practical significance in liver perfusion and in animal pharmacology studies utilizing high t-PA doses.
Tanswell
P
P
Department of Pharmacokinetics, Dr. Karl Thomae GmbH, Biberach an der Riss, Federal Republic of Germany.
Heinzel
G
G
Greischel
A
A
Krause
J
J
D000818:Animals; D002143:Callitrichinae; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010477:Perfusion; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D013045:Species Specificity; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics*
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator