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J Pharm Biomed Anal. 2019 Sep 10;174:734-743. doi: 10.1016/j.jpba.2019.06.045. Epub 2019 Jul 1.

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.

Author information

1
School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China.
2
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, 68198, NE, USA.
3
Department of Molecular and Cell Biology, School of Medicine, University of Connecticut, Storrs, 06269, CT, USA.
4
School of Chemistry and Chemical Engineering, Xuchang University, Xuchang, 461000, China.
5
National Glycoengeering Research Center, Shandong University, No. 44 Wenhuaxi Road, Jinan, 250012, China.
6
School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China. Electronic address: louhongxiang@sdu.edu.cn.

Abstract

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 R D-N, which is a simple and efficient method to rapidly screen potential drug candidates.

KEYWORDS:

Hepatic S9; Macrocyclic bisbibenzyl; Metabolic stability; Metabolites; Riccardin D-N

PMID:
31299454
DOI:
10.1016/j.jpba.2019.06.045

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