Martin U, Fischer S, Kohnert U, Rudolph R, Sponer G, Stern A, Strein K
Department of Pharmacology, Boehringer Mannheim GmbH, Germany.
Thromb Res. 1991 May 1;62(3):137-46. doi: 10.1016/0049-3848(91)90188-3.
The recombinant plasminogen activator BM 06.022 consists of the kringle 2 and the protease domains of human t-PA and is unglycosylated because of its expression in Escherichia coli. The pharmacokinetic properties of BM 06.022 following intravenous injection over 1 min were characterized in anesthetized male New Zealand white rabbits. BM 06.022 was injected at doses of 50, 100, 200, and 400 kU/kg bw (n = 5-6/dose). Activity concentrations in plasma were determined using an indirect spectrophotometric assay. The maximum plasma concentration and the area under the plasma concentration vs. time curve (AUC0-00) of BM 06.022 increased linearly with dose. The systemic clearance ranged from 2.5 to 3.0 ml.min-1.kg-1 and did not show dose-dependency, in contrast to alteplase which was studied at doses of 200, 400, 800, and 1600 kU/kg. A direct comparison of clearance rates of BM 06.022 and alteplase at doses of 200 and 400 kU/kg each revealed a 8.5-fold slower clearance rate of BM 06.022. The majority (18/23) of rabbits with BM 06.022 injection showed a pharmacokinetic profile which was best characterized by a one-compartment model in contrast to alteplase (10/23). The dose-groups of BM 06.022 showed an average dominant half-life ranging from 11.6 to 15.4 min, which was about five-times longer than the dominant half-life values of alteplase (2.3 to 4.5 min). Assuming a two-compartment model in the remaining animals, the initial alpha-phase of BM 06.022 accounted for 40.1 +/- 13.2% (n = 5) of the total AUC, whereas the alpha-phase of alteplase accounted for 82.7 +/- 3% (n = 13) of the total AUC.
重组纤溶酶原激活剂BM 06.022由人组织型纤溶酶原激活剂（t-PA）的kringle 2结构域和蛋白酶结构域组成，由于其在大肠杆菌中表达，因此未进行糖基化修饰。在麻醉的雄性新西兰白兔中研究了BM 06.022静脉注射1分钟后的药代动力学特性。BM 06.022以50、100、200和400 kU/kg体重的剂量注射（每个剂量n = 5 - 6）。使用间接分光光度法测定血浆中的活性浓度。BM 06.022的最大血浆浓度和血浆浓度-时间曲线下面积（AUC0-∞）随剂量呈线性增加。全身清除率范围为2.5至3.0 ml·min-1·kg-1，与阿替普酶不同，未显示出剂量依赖性，阿替普酶的研究剂量为200、400、800和1600 kU/kg。分别在200和400 kU/kg剂量下对BM 06.022和阿替普酶的清除率进行直接比较，结果显示BM 06.022的清除率慢8.5倍。注射BM 06.022的大多数兔子（18/23）呈现的药代动力学特征最适合用单室模型描述，而注射阿替普酶的兔子中这一比例为10/23。BM 06.022的剂量组显示平均主导半衰期范围为11.6至15.4分钟，约为阿替普酶主导半衰期值（2.3至4.5分钟）的五倍。假设其余动物采用双室模型，BM 06.022的初始α相占总AUC的40.1±13.2%（n = 5），而阿替普酶的α相占总AUC的82.7±3%（n = 13）。
