Pharmacokinetics of His-tag recombinant human endostatin in Rhesus monkeys

• 来源期刊: 中国药理学报（英文版）
• 关键词: endostatin pharmacokinetics Macaca mulatta immunoenzyme techniques
• 年，卷（期）: 2005,（1）
• 页码范围: 124-128
• 页数: 5页
• 语种: 英文

摘要

Aim: To study the pharmacokinetics and accumulation of an Escherichia coliexpressed His-tag fused recombinant human endostatin (rh-endostatin) in Rhesus monkeys. Methods: Rh-endostatin was iv or sc injected in Rhesus monkeys, and the rh-endostatin concentration in serum samples was determined by an enzyme immunoassay (EIA) method. The serum drug concentration-time data were analyzed by compartmental analysis using the practical pharmacokinetic program 3p97.Results: Following iv administration at a dose rate of 1.5, 4.5, and 13.5 mg/kg in rhesus monkeys, the concentration-time curves of rh-endostatin were best fitted to a three-compartment open model. AUC(0-∞) linearly increased with dose, while Cls exhibited no significant difference among different dose groups. The terminal half-lives (λ3) were 8±8, 3.1±1.4, and 20±14 h, respectively. After sc administration at a dose rate of 1.5 mg/kg, the concentration-time curve was best fitted to a two-compartment open model, with a terminal half-life (T1/2β) of 8±3 h.Bioavailability following sc injection was approximately 70%±3%. After consecutive iv injection of rh-endostatin at a dose rate of 1.5 mg.kg-1.d-1 for 7 d, the AUC(0-24 h) substantially increased from 22± 13 mg.h.L-1 (d 1) to 50±29 mg.h.L-1 (d 7), with an accumulation factor of 2.3±0.6 (P＜0.05). Conclusion: The pharmacokinetic behavior of rh-endostatin in Rhesus monkeys complies with linear kinetics within the examined dose range. It tends to be accumulated in bodies after repeated administration at a dose level of 1.5 mg.kg-1.d-1 for more than 7 consecutive days.