Determination of the in vitro metabolic stability and metabolites of the anticancer derivative riccardin D-N in human and mouse hepatic S9 fractions using HPLC-Q-LIT-MS

被引：6

作者：

Gao, Yanhui ^{[1
]}

Liu, Ruichen ^{[1
]}

Gautam, Nagsen ^{[2
]}

Ma, Bowen ^{[3
]}

Xie, Zhiyu ^{[4
]}

Sun, Bin ^{[5
]}

Zheng, Hongbo ^{[1
]}

Liu, Dongke ^{[1
]}

Lou, Hongxiang ^{[1
]}

机构：

[1] Shandong Univ, Sch Pharmaceut Sci, 44 Wenhuaxi Rd, Jinan 250012, Shandong, Peoples R China

[2] Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, Omaha, NE 68198 USA

[3] Univ Connecticut, Sch Med, Dept Mol & Cell Biol, Storrs, CT 06269 USA

[4] Xuchang Univ, Sch Chem & Chem Engn, Xuchang 461000, Peoples R China

[5] Shandong Univ, Natl Glycoengn Res Ctr, 44 Wenhuaxi Rd, Jinan 250012, Shandong, Peoples R China

来源：

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS | 2019年 / 174卷

关键词：

Macrocyclic bisbibenzyl; Riccardin D-N; Metabolic stability; Metabolites; Hepatic S9; INFORMATION-DEPENDENT ACQUISITION; MACROCYCLIC BISBIBENZYL COMPOUND; HUMAN LIVER; DRUG-METABOLISM; GROWTH; GLUCURONIDATION; IDENTIFICATION; OPTIMIZATION; PREDICTION; DISCOVERY;

D O I：

10.1016/j.jpba.2019.06.045

中图分类号：

O65 [分析化学];

学科分类号：

070302 ; 081704 ;

摘要：

Riccardin D-N (RD-N) is an aminomethylated derivative of the macrocyclic bisbibenzyl compound riccardin D (RD), which has shown stronger activity against cancer cells than RD. However, there has been no research on the metabolism of RD-N. The present study aimed to characterize the in vitro metabolism and metabolic stability of RD-N after incubation with mouse and human hepatic S9 fractions using high performance liquid chromatography-hybrid triple quadrupole/linear ion trap mass spectrometry (HPLC-Q-LIT-MS). Multiple ion monitoring (MIM) and multiple reaction monitoring (MRM)-information dependent acquisition-enhanced product ion (MIM/MRM-IDA-EPI) scans were used to identify the metabolites formed. MRM scans were also used to quantify the changes in the amount of RD-N and to semi-quantify the main metabolites. Twenty-eight metabolic products were detected and 25 structures were predicted. Hydroxylation, dehydrogenation, glucuronidation, and methylation were proposed to be the principle metabolic pathways in the in vitro incubation with human and mouse hepatic S9 fractions. There were differences in the number and abundance of RD-N metabolites between the human and mouse hepatic S9 fractions. RD-N was shown to have good metabolic stability. After 2 h of incubation, 44% of the original RD-N remained in the human hepatic S9 fraction compared with 22% in the mouse. The major metabolites of RD-N, M4, M8, M20 and M21, were monitored semi-quantitatively using the typical transitions. Finally, HPLC-Q-LIT-MS was used for the identification and quantitation of the metabolites of RD-N, which is a simple and efficient method to rapidly screen potential drug candidates. (C) 2019 Elsevier B.V. All rights reserved.

引用

页码：734 / 743

页数：10