Abstract
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 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.
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Project supported by the National Natural Science Foundation of China, No 39930180.
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Song, Hf., Liu, Xw., Zhang, Hn. et al. Pharmacokinetics of His-tag recombinant human endostatin in Rhesus monkeys. Acta Pharmacol Sin 26, 124–128 (2005). https://doi.org/10.1111/j.1745-7254.2005.00009.x
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DOI: https://doi.org/10.1111/j.1745-7254.2005.00009.x
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