Vaughan D E, Declerck P J, Van Houtte E, De Mol M, Collen D
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Circ Res. 1990 Nov;67(5):1281-6. doi: 10.1161/01.res.67.5.1281.
The pharmacokinetics of human recombinant plasminogen activator inhibitor-1 (rPAI-1) was studied in rabbits. Latent rPAI-1 (0-2 units of tissue-type plasminogen activator neutralizing activity per microgram protein); reactivated rPAI-1 (approximately 150 units/micrograms); and chloramine T-oxidized, nonreactivatable rPAI-1 (approximately 0.7 units/microgram) were studied. The pharmacokinetic parameters for the disposition of rPAI-1 antigen after an intravenous bolus injection of 1.0 or 2.5 mg/kg rPAI-1 were very similar for all three forms: the initial volume of distribution was approximately 60 ml/kg, the initial half-life in plasma was 6 minutes, and the plasma clearance was approximately 4 ml/kg/min. The disposition of PAI activity after injection of reactivated rPAI-1 was similar to that of rPAI-1 antigen. Injection of latent rPAI-1 was associated with a nearly threefold increase in the specific activity of circulating PAI-1 from 2 units/micrograms to 5.0 +/- 1.1 units/micrograms (p less than 0.01) within 1 minute, followed by a cumulative 25-fold increase in specific activity over 1 hour (p = 0.01). In contrast, the specific activity of oxidized or reactivated preparations of rPAI-1 did not increase in the first several minutes after injection. These findings support the existence of a fast-acting but low-capacity mechanism for the reactivation of rPAI-1 in vivo.
在兔体内研究了人重组纤溶酶原激活物抑制剂-1（rPAI-1）的药代动力学。研究了潜在的rPAI-1（每微克蛋白质具有0 - 2单位组织型纤溶酶原激活物中和活性）、重新激活的rPAI-1（约150单位/微克）以及经氯胺T氧化的、不可再激活的rPAI-1（约0.7单位/微克）。静脉推注1.0或2.5 mg/kg rPAI-1后，这三种形式的rPAI-1抗原处置的药代动力学参数非常相似：初始分布容积约为60 ml/kg，血浆初始半衰期为6分钟，血浆清除率约为4 ml/kg/分钟。注射重新激活的rPAI-1后PAI活性的处置与rPAI-1抗原相似。注射潜在的rPAI-1后，循环PAI-1的比活性在1分钟内从2单位/微克增加到5.0±1.1单位/微克，增加了近三倍（p<0.01），随后在1小时内比活性累计增加25倍（p = 0.01）。相比之下，rPAI-1的氧化或重新激活制剂在注射后的最初几分钟内比活性并未增加。这些发现支持体内存在一种快速起效但容量有限的rPAI-1再激活机制。
