Acta Pharmacologica Sinica 2005 January; 26 (1): 124-128; doi: 10.1111/j.1745-7254.2005.00009.x

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-∞) linearly increased with dose, while Cl_s 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 (T_1/2β) 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.