Pharmacokinetics of His-tag recombinant human endostatin in Rhesus monkeys.
OBJECTIVE
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 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).


CONCLUSIONS
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.
Song
Hai-feng
HF
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China. songhf@nic.bmi.ac.cn
Liu
Xiu-wen
XW
Zhang
Hai-ning
HN
Zhu
Bao-zhen
BZ
Yuan
Shou-jun
SJ
Liu
Shang-yi
SY
Tang
Zhong-ming
ZM
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D043169:Endostatins / Q000737:chemistry / Q000493:pharmacokinetics*; D006639:Histidine / Q000737:chemistry; D007275:Injections, Intravenous; D008253:Macaca mulatta; D009842:Oligopeptides / Q000737:chemistry; D011994:Recombinant Proteins / Q000493:pharmacokinetics*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D043169:Endostatins; C471213:His-His-His-His-His-His; D009842:Oligopeptides; D011994:Recombinant Proteins; D006639:Histidine