Pharmacokinetics of His-tag recombinant human endostatin in Rhesus monkeys

• Published in: Acta pharmacologica Sinica Vol. 26; no. 1; pp. 124 - 128
• Main Authors: Song, Hai-feng, Liu, Xiu-wen, Zhang, Hai-ning, Zhu, Bao-zhen, Yuan, Shou-jun, Liu, Shang-yi, Tang, Zhong-ming
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2005
• Subjects: Angiogenesis Inhibitors - pharmacokinetics; Animals; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Biological Availability; Endostatins - chemistry; Endostatins - pharmacokinetics; Escherichia coli; Histidine - chemistry; Injections, Intravenous; Macaca mulatta; Oligopeptides - chemistry; Recombinant Proteins - pharmacokinetics
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1111/j.1745-7254.2005.00009.x

To study the pharmacokinetics and accumulation of an Escherichia coli expressed His-tag fused recombinant human endostatin (rh-endostatin) in Rhesus monkeys. 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. 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-infinity) linearly increased with dose, while Cls exhibited no significant difference among different dose groups. The terminal half-lives (lambda3) 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 (T(1/2beta)) 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). 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.