Visich J E, Byrnes-Blake K A, Lewis K B, Meengs B, Rogge M C
Department of Preclinical Development, ZymoGenetics Inc., Seattle, WA 98102, USA.
J Thromb Haemost. 2006 Sep;4(9):1962-8. doi: 10.1111/j.1538-7836.2006.02097.x. Epub 2006 Jun 22.
Recombinant human thrombin (rhThrombin) is being developed as a general adjunct to hemostasis. Endogenous thrombin is rapidly inactivated by complex formation with antithrombin III and other inhibitors. It follows that these inhibitors will also inactivate any rhThrombin that reaches the systemic circulation.
Study goals were to determine the pharmacokinetic characteristics of [(125)I]-rhThrombin and [(125)I]-rhThrombin complexed to endogenous inhibitors, and the tissue distribution of rhThrombin-associated radioactivity in non-human primates. Hematology, serum chemistry and coagulation status were also monitored.
[(125)I]-rhThrombin was administered intravenously (i.v.; 3.5 U kg(-1)) or subcutaneously (s.c.; 350 U kg(-1)) to male cynomolgus monkeys. Plasma was analyzed for rhThrombin-associated radioactivity and non-compartmental analysis was used to determine the corresponding pharmacokinetic parameters. A size exclusion-high pressure liquid chromatography (SE-HPLC) method was used to quantitate rhThrombin complexes, non-complexed rhThrombin, and free [(125)I]. Whole-body gamma scintigraphy was used to follow radioactivity localization up to 72 h postdose.
No adverse events were observed following [(125)I]-rhThrombin administration. The pharmacokinetic profile of rhThrombin-associated radioactivity following i.v. injection was multi-exponential with an initial half-life of approximately 10 min. Following both i.v. and s.c. dosing, the terminal half-life was approximately 15 h. SE-HPLC analysis revealed that rhThrombin was rapidly complexed to antithrombin III and other inhibitors in the systemic circulation following i.v. administration. Thus, rhThrombin-associated radioactivity in the blood was complexed and presumed inactive. [(125)I]-rhThrombin inhibitor complexes accumulated and were eliminated in the liver following both routes of administration.
These data suggest that rhThrombin rapidly binds to endogenous inhibitors following either i.v. or s.c. administration.
重组人凝血酶（rhThrombin）正在被开发作为止血的一种通用辅助药物。内源性凝血酶会通过与抗凝血酶III及其他抑制剂形成复合物而迅速失活。因此，这些抑制剂也会使任何进入体循环的rhThrombin失活。
研究目标是确定[(125)I]-rhThrombin以及与内源性抑制剂复合的[(125)I]-rhThrombin的药代动力学特征，以及rhThrombin相关放射性在非人类灵长类动物体内的组织分布。同时还监测了血液学、血清化学和凝血状态。
给雄性食蟹猴静脉注射（i.v.；3.5 U kg(-1)）或皮下注射（s.c.；350 U kg(-1)）[(125)I]-rhThrombin。分析血浆中rhThrombin相关放射性，并采用非房室分析来确定相应的药代动力学参数。使用尺寸排阻-高压液相色谱（SE-HPLC）方法对rhThrombin复合物、未复合的rhThrombin和游离[(125)I]进行定量。使用全身γ闪烁显像术追踪给药后长达72小时的放射性定位。
注射[(125)I]-rhThrombin后未观察到不良事件。静脉注射后rhThrombin相关放射性的药代动力学曲线呈多指数形式，初始半衰期约为10分钟。静脉注射和皮下给药后，终末半衰期约为15小时。SE-HPLC分析显示，静脉给药后rhThrombin在体循环中迅速与抗凝血酶III及其他抑制剂形成复合物。因此，血液中rhThrombin相关放射性已形成复合物，推测无活性。[(125)I]-rhThrombin抑制剂复合物在两种给药途径后均在肝脏中蓄积并被清除。
这些数据表明，静脉注射或皮下给药后，rhThrombin会迅速与内源性抑制剂结合。
