van Griensven J M, Koster R W, Hopkins G R, Beier H, Günzler W A, Kroon R, Schoemaker R C, Cohen A F
Centre for Human Drug Research, Leiden, The Netherlands.
Thromb Haemost. 1997 Sep;78(3):1015-20.
The recombinant unglycosylated single chain urokinase-type plasminogen activator saruplase is cleared for a large part by the liver. A large interindividual variation in saruplase concentration is found in acute myocardial infarction (AMI) patients. The variable cardiac performance after an infarct may induce differences in liver blood flow that could explain the concentration diversity. This study was performed to investigate the relation between hepatic blood flow and the pharmacokinetic and pharmacodynamic properties of saruplase.
Thirteen AMI patients were enrolled in this open label study. Patients received a bolus injection of 20 mg saruplase followed by a one-hour infusion of 60 mg saruplase. Concurrently 36 mg intravenous indocyanine green (ICG) was given over 1 h to measure hepatic blood flow. Blood samples were taken at regular time intervals to measure plasma levels of urokinase-type plasminogen activator (u-PA) antigen and activity, the two-chain form (tcu-PA) activity, indocyanine green, fibrinogen, fibrin and fibrin degradation products, alpha2-antiplasmin and thrombin antithrombin III complex. A correlation was seen between the clearance of ICG and both those of u-PA antigen (r = 0.62; p <0.05) and u-PA activity (r = 0.57; p <0.05). A negative correlation was seen between the area under the curve of tcu-PA activity and the areas under the effect curves of both fibrinogen and alpha2-antiplasmin (r = -0.84; p <0.01 and r = -0.65; p <0.05).
Liver blood flow is an important determinant of the clearance of u-PA antigen and activity and reduction of flow in patients with heart failure will lead to an increase in plasma concentrations. High plasma concentrations of tcu-PA activity lead to increased systemic fibrinogenolysis. These results may be used to optimize saruplase treatment in patients with impaired cardiac function or after co-medication with drugs that affect liver blood flow.
重组非糖基化单链尿激酶型纤溶酶原激活剂沙芦普酶大部分经肝脏清除。急性心肌梗死（AMI）患者的沙芦普酶浓度存在较大个体差异。梗死发生后心脏功能的变化可能导致肝血流量的差异，这或许可以解释浓度的多样性。本研究旨在探讨肝血流量与沙芦普酶的药代动力学和药效学特性之间的关系。
13例AMI患者纳入本开放标签研究。患者先静脉推注20mg沙芦普酶，随后1小时输注60mg沙芦普酶。同时，1小时内静脉给予36mg吲哚菁绿（ICG）以测量肝血流量。定期采集血样，检测血浆中尿激酶型纤溶酶原激活剂（u-PA）抗原和活性、双链形式（tcu-PA）活性、吲哚菁绿、纤维蛋白原、纤维蛋白和纤维蛋白降解产物、α2-抗纤溶酶以及凝血酶抗凝血酶III复合物的水平。观察到ICG清除率与u-PA抗原清除率（r = 0.62；p <0.05）和u-PA活性清除率（r = 0.57；p <0.05）之间存在相关性。tcu-PA活性曲线下面积与纤维蛋白原和α2-抗纤溶酶效应曲线下面积之间呈负相关（r = -0.84；p <0.01和r = -0.65；p <0.05）。
肝血流量是u-PA抗原和活性清除的重要决定因素，心力衰竭患者肝血流量减少会导致血浆浓度升高。血浆中高浓度的tcu-PA活性会导致全身纤维蛋白溶解增加。这些结果可用于优化心功能受损患者或与影响肝血流量的药物合用时的沙芦普酶治疗。
