Original Article

Pharmacokinetics of His-tag recombinant human endostatin in Rhesus monkeys1

Hai-feng SONG, Xiu-wen LIU, Hai-ning ZHANG, Bao-zhen ZHU, Shou-jun YUAN, Shang-yi LIU, Zhong-ming TANG


Aim: To study the pharmacokinetics and accumulation of an Escherichia coliexpressed
His-tag fused recombinant human endostatin (rh-endostatin) in Rhesus
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