Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug  

作　　者：Shiwen Song Dong Sun Hong Wang Jinliang Wang Huijing Yan Xuan Zhao John Paul Fawcett Xin Xu Deqi Cai Jingkai Gu 

机构地区：[1]Research Center for Drug Metabolism,School of Life Sciences,Jilin University,Changchun 130012,China [2]Center for Food and Drug Inspection of NMPA,Changchun 130012,China [3]Jen Kem Technology Co.,Ltd.,Tianjin 300450,China [4]State Key Laboratory of Supramolecular Structure and Materials,College of Chemistry,Jilin University,Changchun 130012,China [5]Beijing Institute of Drug Metabolism,Beijing 102209,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第8期3444-3453,共10页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.82030107 and 81872831);the National Science and Technology Major Projects for significant new drugs creation of the 13th five-year plan(2017ZX09101001 and 2018ZX09721002007,China)。

摘　　要：Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,SN-38.Unfortunately,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life and dose-limiting toxicity.To address this problem,a novel trivalent PEGylated prodrug(PEG-[Irinotecan]3)has been synthesized and its full-profile pharmacokinetics,antitumor activity and toxicity compared with those of irinotecan.The results show that after intravenous administration to rats,PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3-x(x=1,2)and PEG-[linker]during which time the released irinotecan undergoes conversion to SN-38.As compared with conventional irinotecan,PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life.In a colorectal cancer-bearing model in nude mice,the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan.In summary,PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan.This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phaseⅡtrial stage.

关 键 词：IRINOTECAN SN-38 Trivalent PEGylated irinotecan PRODRUG Full-profile pharmacokinetics 

分 类 号：R96[医药卫生—药理学]