Pharmacokinetics and biodistribution of a nucleotide-based thrombin inhibitor in rats
Pharmacokinetics and biodistribution of a nucleotide-based thrombin inhibitor in rats
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DOI：
10.1023/a:1011980716659
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发表时间：
1998-06-01
影响因子：
3.7
通讯作者：
Stavchansky, S
中科院分区：
文献类型：
--
作者：
Reyderman, L;Stavchansky, S
目的：研究核苷类凝血酶抑制剂（GS 522，磷酸二酯寡核苷酸，GGTTGGTGTGGTTGG）在大鼠体内的药代动力学和组织分布特征。药代动力学研究：大鼠股静脉快速注射10 mg/kg、20 mg/kg、30 mg/kg（6只动物/剂）。在45分钟内收集血液样品。使用毛细管凝胶电泳-激光诱导荧光检测法测定GS522的血浆浓度。生物分布研究：通过股静脉快速注射给予大鼠10 mg/kg（400 μ l，31.46 μ Ci/ml）H-3-GS 522。分别于给药后1、5、10、30、60、360 min断头处死动物（3只/点），采集脑、血液、十二指肠、眼、心脏、肾脏、肝脏、肺、肌肉、胰腺、皮肤、脾脏和静脉样品，处理并采用液体闪烁计数法定量。药代动力学曲线以多指数方式下降，表现出极快的分布和消除（t（1/2）= 7.6 - 9.0 min，Cl = 22.0 - 28.0 ml/min，V = 83.9 - 132.4 ml/kg）。GS 522遵循线性药代动力学，曲线下面积与剂量成比例（Rsq = 0.9744）。在肾脏、肝脏和血液中检测到最高放射性水平（39.7、15.7和15.3%剂量/相应器官）。在心脏、脾脏和肺中检测到不到1%的剂量，在大脑和眼睛中检测到> 0.3%的剂量。寡核苷酸相关放射性均匀分布在脑区域（左叶和右叶以及小脑）之间。给药后6小时，在脑、眼、皮肤、肝脏、胰腺和静脉中观察到放射性水平的统计学显著增加（p <0.05）。以三种剂量对大鼠静脉给药后的GS522的药代动力学和生物分布特征进行了表征。寡核苷酸相关放射性在组织中广泛分布。在大多数组织中，放射性量随时间急剧下降。肾脏、肝脏和肌肉是主要蓄积部位。寡核苷酸相关放射性未在明显程度上穿过血脑屏障。此外，在选定组织中观察到的放射性水平的统计学显著性增加（p <0.05）表明完整寡核苷酸或其降解产物的再摄取机制。
Purpose, To characterize the pharmacokinetic and tissue distribution profiles of a nucleotide-based thrombin inhibitor (GS522, phosphodiester oligonucleotide, GGTTGGTGTGGTTGG) following intravenous administration to rats.Methods. Pharmacokinetic study: 10 mg/kg, 20 mg/kg, 30 mg/kg (6 animals/dose) were administered to rats by rapid injection into the femoral vein. Blood samples were collected over a 45 minute period. Plasma concentrations of GS522 were determined using capillary gel electrophoresis with laser-induced fluorescence detection. Biodistribution Study: 10mg/kg (400 mu l, 31.46 mu Ci/ml) of H-3-GS522 was administered to rats by rapid injection into the femoral vein. The animals were sacrificed by decapitation at 1, 5, 10, 30, 60, 360 minutes post-dose (3 rats/point), Brain, blood, duodenum, eyes, heart, kidney, liver, lungs, muscle, pancreas, skin, spleen and vein samples were collected, processed and quantitated using liquid scintillation counting.Results. The pharmacokinetic profile declines in multiexponential manner, exhibiting extremely fast distribution and elimination (t(1/2) = 7.6-9.0 min, Cl = 22.0-28.0 ml/min, V = 83.9-132.4 ml/kg). GS522 follows linear pharmacokinetics, with the area under the curve being proportional to the dose (Rsq = 0.9744). Highest radioactivity levels were detected in kidney, liver and blood (39.7, 15.7 and 15.3% dose/ respective organ). Less than 1% of the dose was detected in the heart, spleen and lungs, and >0.3% of the dose was found in the brain and eyes. The oligonucleotide associated radioactivity was uniformly distributed between the brain regions (left and right lobe and cerebellum). Six hours following the dose administration a statistically significant increase (p < 0.05)in radioactivity levels was observed in the brain, eyes, skin, liver, pancreas and vein.Conclusions. The pharmacokinetic and biodistribution profiles of GS522 following intravenous administration to rats at three doses were characterized. The oligonucleotide associated radioactivity was widely distributed in tissues. The amount of radioactivity sharply decreased with time in most tissues. Kidney, liver and muscle were the main sites of accumulation. The oligonucleotide associated radioactivity did not cross the blood brain barrier to an appreciable extent. In addition, a statistically significant increase (p < 0.05) in the radioactivity levels observed in select tissues suggested a re-uptake mechanism for intact oligonucleotide or its degradation products.