The recombinant
plasminogen activator BM 06.022 consists of the kringle 2 and the
protease domains of human t-PA and is unglycosylated because of the expression in Escherichia coli. The thrombolytic and pharmacokinetic properties as well as the hemostasis effects of
BM 06.022 were investigated in the rabbit model of jugular vein
thrombosis. The thrombi were 125I-fibrin labeled. Intravenous bolus injection of 50, 100, 200, and 400 kU/kg
BM 06.022 or 400, 800, and 1600 kU/kg
alteplase over 15 s to six rabbits/dose produced a dose-dependent increase of thrombolysis determined 2 h post injection. The dose-response curve of
BM 06.022 was located left compared with that of
alteplase. The effective dose of 50% thrombolysis (ED50) obtained by half-logarithmic regression analysis was 163 kU/kg (= 0.28 mg/kg) for
BM 06.022 and 871 kU/kg (= 1.09 mg/kg) for
alteplase. At equipotent doses (50% thrombolysis), the residual concentration of
fibrinogen was 74.2% and 76.5%, that of
plasminogen 66.7% and 69.4%, and that of alpha 2-antiplasmin 47.3% and 46% for
BM 06.022 and
alteplase, respectively. Pharmacokinetic analysis for plasma activity at a dose of 400 kU/kg revealed a half-life of 18.9 +/- 1.5 min for
BM 06.022, whereas
alteplase was distributed with a half-life of 2.1 +/- 0.1 min, accounting for 86.7 +/- 1.9% of the total AUC, followed by a beta-phase with a half-life of 13.8 +/- 0.9 min. Plasma clearance of
BM 06.022 was 4.7 +/- 0.7 ml min-1 kg-1 compared with 20 +/- 1.2 ml min-1 kg-1 for
alteplase.(ABSTRACT TRUNCATED AT 250 WORDS)