Boneu B, Caranobe C, Gabaig A M, Dupouy D, Sie P, Buchanan M R, Hirsh J
Thromb Res. 1987 Jun 15;46(6):835-44. doi: 10.1016/0049-3848(87)90075-2.
This work demonstrates that after bolus intravenous injection standard heparin (SH) disappearance results from the combination of a saturable and a non saturable mechanism. Pharmacokinetics and pharmacodynamics of SH were studied by measuring the disappearance of increasing doses (5 - 500 anti-factor Xa U/kg) of 125I-heparin and of its biological effects. CPM curves allowed to determine the half lives of heparin according to the dose injected. The half lives were clearly dose dependent and reached a plateau over 100 anti-factor Xa U/kg. The complex curve which describes the amount of heparin cleared per time unit after any given dose has been resolved into its two components reflecting a saturable and a non saturable mechanism of disappearance. For the doses less than 100 anti-factor Xa U/kg the saturable mechanism was preeminent and the anti-factor Xa activity disappearance followed an exponential pattern; for the doses less than 100 anti-factor Xa U/kg the contribution of the non saturable mechanism becomes more important and the anti-factor Xa activity disappearance followed a concave-convex pattern. Further experiments showed that the heparin half life shortened as the circulating anti-factor Xa activity decreased; this phenomenon may explain the concave-convex pattern of the curve of the anticoagulant effect observed after injection of large doses of SH.
这项研究表明，静脉推注标准肝素（SH）后，其消失是由可饱和和不可饱和机制共同作用的结果。通过测量递增剂量（5 - 500抗Xa因子单位/千克）的125I-肝素及其生物学效应的消失情况，研究了SH的药代动力学和药效学。计数率曲线有助于根据注射剂量确定肝素的半衰期。半衰期明显依赖于剂量，在超过100抗Xa因子单位/千克时达到平台期。描述在任何给定剂量后单位时间内清除的肝素量的复杂曲线已分解为反映可饱和和不可饱和消失机制的两个组成部分。对于小于100抗Xa因子单位/千克的剂量，可饱和机制占主导，抗Xa因子活性的消失呈指数模式；对于大于100抗Xa因子单位/千克的剂量，不可饱和机制的作用变得更加重要，抗Xa因子活性的消失呈凹凸模式。进一步的实验表明，随着循环抗Xa因子活性降低，肝素半衰期缩短；这种现象可能解释了注射大剂量SH后观察到的抗凝效应曲线的凹凸模式。
