Pharmacokinetics of His-tag recombinant human endostatin in Rhesus monkeys

Aim: To study the pharmacokinetics and accumulation of an Escherichia coli-expressed 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-infinity)) linearly increased with dose, while CI5 exhibited no significant difference among different dose groups. The terminal half-lives (gimel(3)) 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((0-24h)) 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.