Zuo-gang Li1, Lin Jia2, Li-fang Guo3, Min Yu1, Xu Sun1, Wen Nie1, Yan Fu2, Chun-ming Rao4, Jun-zhi Wang4, Yong-zhang Luo2. 1. China's National Center for Safety Evaluation of Drugs, Beijing 100050, China. 2. 1] National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China [2] Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China [3] Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China. 3. 1] Peking Union Medical College, Tsinghua University, Beijing 100084, China [2] National Institutes for Food and Drug Control, Tsinghua University, Beijing 100084, China. 4. National Institutes for Food and Drug Control, Tsinghua University, Beijing 100084, China.
Abstract
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.
AIM: M2ES is PEGylated recombinant humanendostatin. 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 humanendostatin 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.
Authors: L Taddei; P Chiarugi; L Brogelli; P Cirri; L Magnelli; G Raugei; M Ziche; H J Granger; V Chiarugi; G Ramponi Journal: Biochem Biophys Res Commun Date: 1999-09-24 Impact factor: 3.575
Authors: G Molema; I van Veen-Hof; A M van Loenen-Weemaes; J H Proost; L F de Leij; D K Meijer Journal: Int J Cancer Date: 2001-01-01 Impact factor: 7.396