Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug.
10.1016/j.apsb.2023.01.011
- Author:
Shiwen SONG
1
;
Dong SUN
1
;
Hong WANG
1
;
Jinliang WANG
2
;
Huijing YAN
2
;
Xuan ZHAO
2
;
John Paul FAWCETT
1
;
Xin XU
1
;
Deqi CAI
1
;
Jingkai GU
1
Author Information
1. Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China.
2. JenKem Technology Co., Ltd., Tianjin 300450, China.
- Publication Type:Journal Article
- Keywords:
Full-profile pharmacokinetics;
Irinotecan;
Prodrug;
SN-38;
Trivalent PEGylated irinotecan
- From:
Acta Pharmaceutica Sinica B
2023;13(8):3444-3453
- CountryChina
- Language:English
-
Abstract:
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 phase II trial stage.
