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Published on: September 1, 2016
Pharmacokinetics of PEGylated recombinant human endostatin (M2ES) in rats
Zuo-gang Li1, Lin Jia2, Li-fang Guo3
1China's National Center for Safety Evaluation of Drugs, Beijing 100050, China.
Aim:
M2ES is PEGylated recombinant human endostatin. In this study we investigated the pharmacokinetics, tissue distribution, and excretion of M2ES in rats.
Methods:
(125)I-radiolabeled M2ES was administered to rats by intravenous bolus injection at 3 mg/kg. The pharmacokinetics, tissue distribution and excretion of M2ES were investigated using the trichloroacetic acid (TCA) precipitation method.
Results:
The serum M2ES concentration-time curve after a single intravenous dose of 3 mg/kg in rats was fitted with a non-compartment model. The pharmacokinetic parameters were evaluated as follows: Cmax=28.3 μg·equ/mL, t1/2=71.5 h, AUC(0-∞)=174.6 μg·equ·h/mL, Cl=17.2 mL·h(-1)·kg(-1), MRT=57.6 h, and Vss=989.8 mL/kg for the total radioactivity; Cmax=30.3 μg·equ/mL, t1/2=60.1 h, AUC(0-∞)=146.2 μg·equ·h/mL, Cl=20.6 mL·h(-1)·kg(-1), MRT=47.4 h, and Vss=974.6 mL/kg for the TCA precipitate radioactivity. M2ES was rapidly and widely distributed in various tissues and showed substantial deposition in kidney, adrenal gland, lung, spleen, bladder and liver. The radioactivity recovered in the urine and feces by 432 h post-dose was 71.3% and 8.3%, respectively. Only 0.98% of radioactivity was excreted in the bile by 24 h post-dose.
Conclusion:
PEG modification substantially prolongs the circulation time of recombinant human endostatin and effectively improves its pharmacokinetic behavior. M2ES is extensively distributed in most tissues of rats, including kidney, adrenal gland, lung, spleen, bladder and liver. Urinary excretion was the major elimination route for M2ES.
Insights
PEGylated recombinant human endostatin (M2ES) shows prolonged circulation and wide tissue distribution in rats. Urinary excretion is the primary elimination route for this endostatin derivative.
Area of Science:
- Pharmacology and Drug Development
- Biotechnology
- Biochemistry
Background:
- Recombinant human endostatin is a potent anti-angiogenic agent.
- PEGylation is a common strategy to improve the pharmacokinetic properties of protein therapeutics.
Purpose of the Study:
- To investigate the pharmacokinetics, tissue distribution, and excretion of PEGylated recombinant human endostatin (M2ES) in rats.
- To evaluate the impact of PEGylation on the in vivo behavior of endostatin.
Main Methods:
- (125)I-radiolabeled M2ES was administered intravenously to rats at a dose of 3 mg/kg.
- Pharmacokinetics, tissue distribution, and excretion were assessed using the trichloroacetic acid (TCA) precipitation method.
Main Results:
- M2ES exhibited a prolonged half-life (t1/2) of approximately 71.5 hours.
- The drug was widely distributed in various tissues, with significant accumulation in the kidney, adrenal gland, lung, spleen, bladder, and liver.
- Urinary excretion accounted for the majority of the administered dose (71.3% by 432 hours), with fecal excretion at 8.3%.
Conclusions:
- PEG modification significantly enhances the pharmacokinetic profile of recombinant human endostatin.
- M2ES demonstrates extensive tissue distribution in rats.
- Urinary excretion is the predominant route of M2ES elimination.
