Pharmacokinetics of single chain forms of urokinase-type plasminogen activator

DC Stump, L Kieckens, F De Cock and D Collen

The pharmacokinetics of single chain urokinase-type plasminogen activator (scu-PA) were studied in rabbits and squirrel monkeys using three of its molecular forms, Mr 54,000 isolated from human urine (urinary scu-PA), Mr 54,000 isolated from conditioned media of cultured human lung adenocarcinoma cells (CALU-3) (cellular scu-PA) and its Mr 32,000 proteolytic derivative lacking the NH2-terminal 143 amino acids (scu-PA-32k). After bolus i.v. injection in rabbits with 2.5 kg. b.wt., the disappearance rate of all three forms from plasma could be described by a two-compartment disposition model with the following pharmacokinetic parameters: alpha T1/2, 3.2 to 3.9 min; beta T1/2, 15 to 16 min; volume of the central compartment, 170 to 200 ml; total volume of distribution, 660 to 910 ml; and plasma clearance, 18 to 22 ml/min. Similar results were obtained with cellular scu-PA in squirrel monkeys. Plasma euglobulin fibrinolytic activity disappeared in parallel with antigen, suggesting that the primary mechanism of disappearance is via clearance of the intact molecule. The organ distribution of isotope after bolus injection of 125I-labeled scu-PA revealed that clearance occurred via the liver and kidneys in rabbits, but predominantly via the liver in squirrel monkeys. Functional hepatectomy prolonged the alpha T1/2 of scu-PA in rabbits, whereas nephrectomy had no significant effect. Steady-state plasma levels of scu-PA during continuous i.v. infusion were proportional to the dose given, whereas the initial postinfusion disappearance rate of scu-PA from plasma was comparable to that after bolus injection (T1/2 of 5 to 6 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 242, Issue 1, pp. 245-250, 07/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics