van Griensven J M, Huisman L G, Stuurman T, Dooijewaard G, Kroon R, Schoemaker R C, Kluft K, Cohen A F
Centre for Human Drug Research, Leiden, The Netherlands.
Clin Pharmacol Ther. 1996 Nov;60(5):504-11. doi: 10.1016/S0009-9236(96)90146-0.
To investigate the influence of increased liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue-type plasminogen activator (rt-PA) and to study the changes in endogenous urokinase-type plasminogen activator (u-PA).
This open, randomized, crossover trial was carried out in a clinical research unit. Eight healthy, nonsmoking volunteers received linear infusions of 24 mg rt-PA and 92 mg indocyanine green over 160 minutes. Sixty minutes after the infusions were started, the subjects consumed a standardized meal to increase liver blood flow on one occasion and abstained from taking food on the other occasion. Plasma concentrations of indocyanine green, tissue-type plasminogen activator (t-PA) antigen, t-PA activity, total u-PA antigen, plasmin-activatable single-chain u-PA (scu-PA), active two-chain u-PA (tcu-PA), fibrinogen, total fibrin, and fibrinogen/fibrin degradation products (TDP), and alpha 2-antiplasmin were measured.
After the consumption of the meal, the area under the curve (AUC) was 35% (95% confidence interval [CI]: 25%, 43%) lower for indocyanine green, 15% (CI: 6%, 24%) lower for t-PA antigen, and 11% (CI: 2%, 19%) lower for t-PA activity compared to the AUC after subjects abstained from food. No changes were observed in fibrinogen, TDP, or alpha 2-antiplasmin concentrations that were attributable to the intake of food. The infusion of rt-PA caused a fivefold increase in the concentration of active tcu-PA and a concomitant decrease in scu-PA concentrations by more than 50%.
Increased liver blood flow results in an increase in t-PA clearance. The conversion of the inactive zymogen scu-PA to the active tcu-PA is increased by an infusion of rt-PA, but total u-PA antigen concentrations remain unchanged.
研究肝脏血流增加对重组组织型纤溶酶原激活剂（rt-PA）药代动力学和药效学的影响，并探讨内源性尿激酶型纤溶酶原激活剂（u-PA）的变化。
本开放性、随机、交叉试验在临床研究单位进行。8名健康、不吸烟的志愿者在160分钟内接受24mg rt-PA和92mg吲哚菁绿的静脉滴注。输注开始60分钟后，受试者一次食用标准化餐食以增加肝脏血流，另一次不进食。测定血浆中吲哚菁绿、组织型纤溶酶原激活剂（t-PA）抗原、t-PA活性、总u-PA抗原、纤溶酶可激活的单链u-PA（scu-PA）、活性双链u-PA（tcu-PA）、纤维蛋白原、总纤维蛋白、纤维蛋白原/纤维蛋白降解产物（TDP）以及α2-抗纤溶酶的浓度。
与不进食后相比，进食后吲哚菁绿的曲线下面积（AUC）降低35%（95%置信区间[CI]：25%，43%），t-PA抗原降低15%（CI：6%，24%），t-PA活性降低11%（CI：2%，19%）。未观察到纤维蛋白原、TDP或α2-抗纤溶酶浓度因进食而发生变化。rt-PA输注导致活性tcu-PA浓度增加5倍，同时scu-PA浓度降低超过50%。
肝脏血流增加导致t-PA清除率增加。rt-PA输注可使无活性的酶原scu-PA向活性tcu-PA的转化增加，但总u-PA抗原浓度保持不变。
