Brieger D, Dawes J
Applied Research Group, Heart Research Institute, Sydney, Australia.
Thromb Haemost. 1997 Feb;77(2):317-22.
Low molecular weight (LMW) heparins have prolonged circulating half-lives relative to unfractionated heparin, but the rates of plasma clearance differ between different LMW preparations. To determine the impact of method of production on their pharmacokinetic and ex vivo biological properties, two LMW heparins of similar molecular weight distribution, Logiparin and Fragmin, were radiolabelled with 125I, administered intravenously with 4 mg/kg of carrier drug into rabbits, and the circulating radiolabelled material and anti-Xa activity were analysed by size exclusion chromatography and affinity for antithrombin and Polybrene. Following administration of Logiparin, the anti-Xa amidolytic activity was eliminated with the same half-life as the anti-thrombin-binding radiolabel and was not neutralised by antibody against tissue factor pathway inhibitor (TFPI). Larger molecules were cleared preferentially and were no longer detectable 8 h post injection. These findings resemble those we have previously described for Enoxaparin. After Fragmin administration the antithrombin binding radiolabel was cleared more rapidly than the anti-Xa activity, and at late times after injection a significant amount of this activity was neutralised by antibody against TFPI. Sulphated radiolabel was eliminated with a similar half-life to the anti-Xa activity and sulphated molecules > 6000 Da remained in the circulation 8 h after administration. Fragmin, unlike Logiparin and Enoxaparin, has no negatively charged sulphamino group at the reducing end of the molecule. We suggest that this minimises cellular interaction and protects the larger molecules from elimination. They remain in the circulation, contributing to anti-Xa activity by binding TFPI. Thus the method of production of LMW heparins may significantly influence their pharmacokinetic properties and circulating anticoagulant activities.
与普通肝素相比，低分子量（LMW）肝素具有更长的循环半衰期，但不同LMW制剂的血浆清除率有所不同。为了确定生产方法对其药代动力学和体外生物学特性的影响，将两种分子量分布相似的LMW肝素（洛吉肝素和达肝素）用125I进行放射性标记，以4mg/kg的载体药物静脉注射给兔子，并通过尺寸排阻色谱法以及对抗凝血酶和鱼精蛋白的亲和力分析循环中的放射性标记物质和抗Xa活性。注射洛吉肝素后，抗Xa酰胺水解活性与抗凝血酶结合放射性标记物以相同的半衰期消除，并且未被针对组织因子途径抑制剂（TFPI）的抗体中和。较大的分子优先被清除，注射后8小时不再可检测到。这些发现与我们之前描述的依诺肝素的发现相似。注射达肝素后，抗凝血酶结合放射性标记物的清除速度比抗Xa活性更快，并且在注射后的后期，大量这种活性被针对TFPI的抗体中和。硫酸化放射性标记物的消除半衰期与抗Xa活性相似 > 6000Da的硫酸化分子在给药后8小时仍留在循环中。与洛吉肝素和依诺肝素不同，达肝素在分子的还原端没有带负电荷的磺氨基。我们认为，这使细胞相互作用最小化，并保护较大的分子不被清除。它们保留在循环中，通过结合TFPI促进抗Xa活性。因此，LMW肝素的生产方法可能会显著影响其药代动力学特性和循环抗凝活性。
