Biological and thrombolytic properties of proenzyme and active forms of human urokinase--II. Turnover of natural and recombinant urokinase in rabbits and squirrel monkeys
Collen, D.; De Cock, F.; Lijnen, H.R.
Thrombosis and Haemostasis 52(1): 24-26
1984
ISSN/ISBN: 0340-6245 PMID: 6495260 Document Number: 228502
The turnover of recombinant pro-urokinase (Rec-pro-UK), recombinant urokinase (Rec-UK) and natural urinary urokinase (Nat-UK) was studied in rabbits and in squirrel monkeys (Samiri sciureus). Following i.v. injection, urokinase activtiy disappeared rapidly from the blood. The initial disappearance rate could be described by a single exponential term with a t1/2 [half-life] of 3 to 6 min for each molecular form of urokinase in both species. Urokinase-related antigen, measured with a radioimmunoassay in the plasma of the squirrel monkeys disappeared with a t1/2 of 3.5 min for Rec-pro-UK, 6.0 min for Rec-UK and 8.0 min for Nat-UK. The clearance and organ distribution of Rec-pro-UK, Rec-UK and Nat-UK were studied with the use of 125I-labeled preparations. In each case the radioactivity initially disappeared rapidly from the plasma, also with a t1/2 of a few min, but then the disappearance rate slowed down. Labeled Rec-UK in which the active site histidine was irreversibly blocked by alkylation, disappeared equally rapidly from the plasma. Measurement of the organ distribution of 125I at different time intervals revealed that all 3 types of urokinase were rapidly accumulated in the liver, which was followed by release of degradation products in the blood. Experimental hepatectomy prolonged the t1/2 of each type of urokinase very markedly (t1/2 > 30 min). Urokinase is rapidly removed from the blood by clearance and degradation in the liver. Recognition by the liver does not require a functional active site and is not mediated via carbohydrate side chains. Inactivation by plasma protease inhibitors does not represent a significant pathway of urokinase inhibition in vivo.