Pharmacokinetics Of Recombinant Human Glycosylated Single-chain Urokinase-type Plasminogen Activator(u-PA)and Its Effects On Fibrinolytic Parameters In Chinese Healthy Subjects

Part 1 Objective To evaluate the tolerance, safety and effects on fibrinolytic parameters of recombinant human glycosylated singlehain urokinaseype plasminogen activator (uA). Methods uA was injected intravenously to 24 Chinese healthy volunteers who were divided into four groups: 24 cases, randomly divided into four groups, 5mg, 20mg, 35mg and 50 mg. Results There were no abnormal changes in blood pressure, heart rate, and respiration rate of all subjects. There were also no significant difference in blood parameters related to thrombolysis (prothrombin time ,activated partial thromboplatin time, fibrinogen ,plasminogen, a 2? antiplasmin) ,blood routine, urine routine, hepatic and renal functions,electrolytes and fasting blood suger.no bleeding was found in all 24 cases. Conclusion Chinese healthy volunteers have a good tolerance to the above dose of uA. Part 2 Objective To study the pharmacokinetics of recombinant human glycosylated singlehain urokinaseype plasminogen activator (uA) by intravenous S administration in healthy Chinese subjects. Methods 20mg of uA were given to 7 subjects (4 males & 3 females) 35mg of uA were given to 6 subjects ( 3 males & 3 females ) , and 50mg of uA were given to 6 subjects (4 males & 3 females) separately. The times of taking blood were0, 0. 02, 0. 08, 0. 17, 0. 33, 0. 67, 1. 0, 1. 08, 1. 5, 2. 0, 2. 5,4. 0, 6 ?0 and 24. 0 hour after intravenous administration. The plasma concentration of uA, scuA were detected by ELJSA. Results In 20mg group, Cof uA, scuA & fibrinolytic effect were 91?6 ng/Ml, 82?7 ng/Ml & 0.62? 0. 70 lU/Mi; In 35mg group , C55 of uA, scuA & fibrinolytic effect werel95?04 ng/Ml , 162?68 ng/Ml & 2. 1?. 0 IU/Ml; In 50mg group , C~ of uA, scuA & fibrinolytic effect were340?60 ng/Ml , 246?96 ng/Ml & 23?5 IU/mL. The C55 of uA, scuA & fibrinolytic effect were increased doseependently (P < 0. 001) After discontinuation of the infusion, there were the rapid decline followed by the slower phase; at the sixth hour after the uA intravenous administration start, the concentration of uA, scuA & fibrinolytic effect were returned to the level before the uA intravenous administration start. In 20mg group, the concentration of scuA the concentration of uA, almost no tcuA converted from scuA; the concentration of scuA<( the concentration of uA in 35mg & 50mg group (P < 0.001), the quantity of tcuA converted from scuA were increased doseependently. So did their fibrinolytic 9 1?~t~ effect. The quantity of tcuA converted from scuA were increased doseependently: In 20mg group, almost no tcu? PA converted from scuA; In 35mg group & 50mg group, 15.4 % I 4.2 % & 27.9 % ~ 7.0 % tcuA increased (converted from scuA), P < 0.001. In 20mg group, 35mg group & 50mg group, AUC(o-6) : uA were 216. 9 ?50. 6 ng.h.mI.7? 501.3 1 152.5 ng.h.m171& 638.2 ?62.7 ng.h.mU 1(1 : 2. 31 : 2. 94) ; AUC(o~6) : scuA were 227. 2 ?43. 1 ng.h.mlP, 424.8 ?133.6 ng.h.nil.7? 457.1 ?26.5 ng.h.mU i( 1 : 1.87 : 2.01); AUC(o-6, : fibrinolytic effect were 0.90 ?0.33 IU.h.mJ.11, 3.2 ?1.0 IU.h.mL1 & 37.8 ?7.8 IU. h. mU1 (1 : 3. 55 : 42) AUC(~6) : uA, AUC(96...