Grindel J M, Musick T J, Jiang Z, Roskey A, Agrawal S
Hybridon, Inc., Cambridge, MA 02139, USA.
Antisense Nucleic Acid Drug Dev. 1998 Feb;8(1):43-52. doi: 10.1089/oli.1.1998.8.43.
The pharmacokinetics and metabolism of an antisense oligonucleotide phosphorothioate (GEM91) were studied in cynomolgus monkeys following intravenous infusion. [35S]-Labeled GEM91 was administered to 12 monkeys by means of a 2-hour intravenous infusion at a dose of 4 mg/kg. Plasma pharmacokinetic analysis revealed that the maximum plasma concentration was 41.7 microg equivalents/ml, which was achieved in 2.13 hours. The plasma elimination half-life was 55.8 hours based on radioactivity levels. Urinary excretion represented the major pathway of elimination, with 70% of the administered dose excreted in urine over 240 hours. The oligonucleotide was widely distributed to tissues. The highest concentrations were observed in the liver and kidney. Analysis of the extracted oligonucleotide following post-labeling with [32p] on polyacrylamide gel electrophoresis showed the presence of both intact and degraded oligonucleotide in plasma, kidney, liver, spleen, and lymph nodes. Based on the methods used for post-labeling (either 3'-end or 5'-end), different patterns of bands were observed on polyacrylamide gel electrophoresis, suggesting metabolic modification of the administered oligonucleotide.
在食蟹猴静脉输注后，研究了反义寡核苷酸硫代磷酸酯（GEM91）的药代动力学和代谢情况。通过2小时静脉输注以4mg/kg的剂量给12只猴子施用[35S]标记的GEM91。血浆药代动力学分析显示，最大血浆浓度为41.7μg当量/ml，在2.13小时达到。基于放射性水平，血浆消除半衰期为55.8小时。尿排泄是主要的消除途径，在240小时内70%的给药剂量经尿液排出。该寡核苷酸广泛分布于组织中。在肝脏和肾脏中观察到最高浓度。在用[32P]进行后标记后，在聚丙烯酰胺凝胶电泳上对提取的寡核苷酸进行分析，结果显示在血浆、肾脏、肝脏、脾脏和淋巴结中同时存在完整的和降解的寡核苷酸。基于用于后标记的方法（3'-末端或5'-末端），在聚丙烯酰胺凝胶电泳上观察到不同的条带模式，提示所施用的寡核苷酸发生了代谢修饰。
