Martin U, Sponer G, Strein K
Department of Pharmacology, Boehringer Mannheim GmbH, Mannheim, Germany.
Drug Metab Dispos. 1993 Mar-Apr;21(2):236-41.
BM 06.022 is a novel recombinant, unglycosylated plasminogen activator comprising only the kringle 2 and protease domains of human tissue-type plasminogen activator (t-PA), and it has a longer half-life than t-PA. Because t-PA is mainly cleared by the liver, rat models of hepatic and renal insufficiency were used to identify the main catabolic organ of BM 06.022, compared with alteplase (recombinant t-PA). Hepatic insufficiency in rats was chemically induced by pretreatment with carbon tetrachloride for 1 day; renal insufficiency was achieved by acute bilateral, surgical nephrectomy. Plasma concentration of functionally active BM 06.022 or alteplase was measured by an indirect spectrophotometric assay. Intravenous administration of 200 kU/kg of BM 06.022 or alteplase over 15 sec to rats with hepatic failure or olive oil pretreatment as control did not significantly alter the total plasma clearance (CL) of BM 06.022 vs. control (4.9 +/- 0.5 vs. 5.7 +/- 0.5 ml.min-1 x kg-1, NS) in contrast to alteplase (32.1 +/- 6.5 vs. 82.3 +/- 12.9 ml.min-1 x kg-1, p < 0.05). Renal insufficiency increased the CL of BM 06.022 vs. sham surgery (3.1 +/- 0.4 vs. 6.3 +/- 0.5 ml.min-1 x kg-1, p < 0.05) in contrast to alteplase (33.2 +/- 5.2 vs. 37.2 +/- 7.2 ml.min-1 x kg-1, NS). In vitro incubation of 2000 U/ml BM 06.022 or alteplase in citrate blood and plasma demonstrated a decrease of the plasma concentration with a shorter (p < 0.001) half-life for BM 06.022 than for alteplase in blood (71.9 +/- 3.1 vs. 130 +/- 3.3 min) and in plasma (62.9 +/- 1.2 vs. 129.9 +/- 5.3 min).(ABSTRACT TRUNCATED AT 250 WORDS)
BM 06.022是一种新型重组、未糖基化的纤溶酶原激活剂，仅包含人组织型纤溶酶原激活剂（t-PA）的kringle 2和蛋白酶结构域，其半衰期比t-PA更长。由于t-PA主要由肝脏清除，因此使用肝肾功能不全的大鼠模型来确定BM 06.022的主要分解代谢器官，并与阿替普酶（重组t-PA）进行比较。大鼠的肝损伤通过四氯化碳预处理1天化学诱导；肾损伤通过急性双侧手术切除肾脏实现。通过间接分光光度法测定功能活性BM 06.022或阿替普酶的血浆浓度。在15秒内给肝功能衰竭的大鼠静脉注射200 kU/kg的BM 06.022或阿替普酶，或用橄榄油预处理作为对照，结果显示与对照相比，BM 06.022的总血浆清除率（CL）没有显著变化（4.9±0.5对5.7±0.5 ml·min⁻¹·kg⁻¹，无统计学差异），而阿替普酶有显著变化（32.1±6.5对82.3±12.9 ml·min⁻¹·kg⁻¹，p<0.05）。与假手术相比，肾功能不全增加了BM 06.022的CL（3.1±0.4对6.3±0.5 ml·min⁻¹·kg⁻¹，p<0.05），而阿替普酶没有变化（33.2±5.2对37.2±7.2 ml·min⁻¹·kg⁻¹，无统计学差异）。在柠檬酸盐血液和血浆中对2000 U/ml的BM 06.022或阿替普酶进行体外孵育，结果显示血浆浓度降低，BM 06.022在血液中的半衰期（71.9±3.1对130±3.3分钟）和血浆中的半衰期（62.9±1.2对129.9±5.3分钟）均短于阿替普酶（p<0.001）。（摘要截断于250字）
