In vitro metabolism and drug-drug interaction potential of IG-105, a novel antimicrotubule agent
10.16438/j.0513-4870.2017-0467
- VernacularTitle:新型抗肿瘤微管抑制剂IG-105的体外代谢及药物相互作用的研究
- Author:
Jing PANG
1
;
Xin-xin HU
1
;
Yue-ming WANG
1
;
Cong-ran LI
1
;
Xin-yi YANG
1
;
Zong-ying LIU
1
;
Lai-xing HU
1
;
Dan-qing SONG
1
;
Zhuo-rong LI
1
;
Xue-fu YOU
1
;
Jian-dong JIANG
2
Author Information
1. Beijing Key Laboratory of Antimicrobial Agents and Department of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Publication Type:ORIGINAL ARTICLES
- Keywords:
IG-105;
anticancer;
in vitro metabolism;
drug-drug interaction
- From:
Acta Pharmaceutica Sinica
2017;52(6):921-927
- CountryChina
- Language:Chinese
-
Abstract:
IG-105, N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide, a novel antimicrotubule agent, showed potent anticancer activity in a variety of human tumor cells in vitro and in vivo. In order to characterize the metabolism and the possible drug-drug interaction of IG-105, we carried out a series of experiments. Drug metabolizing enzymes involved in IG-105 metabolism were investigated by using pooled human liver microsomes (HLMs) and recombinant cytochrome P450 isoforms (rP450s) respectively. The possible metabolites were analyzed by liquid chromatography-orbitrap-mass spectrometry (LC-Orbitrap-MS). The inhibitory effect of IG-105 on main P450 enzymes was also evaluated. The results showed that IG-105 can be metabolized by a series of rP450s, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, with the major contribution enzymes being CYP1A2, CYP2B6, CYP2C19, and CYP3A. Three metabolites (M1-M3) were identified and demethylation was the major phase I metabolic reaction for IG-105. IG-105 moderately inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A enzyme activities with IC50 values of 6.42, 23.64, 0.39, 1.4, and 3.14 μmol·L-1, respectively. Since the biotransformation of IG-105 involves multiple enzymatic pathways, the compound is less likely to be a victim of a concomitantly used medicine which inhibits activity of one of the CYPs. However, as IG-105 showed medium to strong inhibition on CYP1A2, CYP2D6, CYP3A, and CYP2C19, caution is particularly needed when IG-105 is co-administrated with other anticancer drugs which are mainly metabolized by the above enzymes.
