Metabolic profiling in liver microsomes and mice of E28, a potent FLT3 inhibitor

Abstract

1. The objective of this study was to clarify the species differences of metabolic stability of E28 in liver microsomes, and to study metabolic phenotypes of E28 in human liver microsomes by chemical inhibition method.

2. The metabolites in plasma, urine, and faeces samples from mice received caudal vein intravenous were detected and identified by UHPLC–HRMS, and the tissue distribution was studied after oral administration.

3. E28 was metabolised rapidly in liver microsomes of each species with a short half-live T_1/2 and a moderate clearance, except for rats. The metabolic properties of E28 were similar in human and mouse liver microsomes. Data from metabolic phenotype studies indicated that CYP2D6, CYP3A4 and CYP2C9 were the main metabolic enzymes participating in the metabolism of E28.

4. The main metabolic pathways implicated include oxidation, methylation, amide hydrolysis, acetylation, glucuronide conjugation.

5. Tissue distribution studies showed that E28 could be detected in all organs and tissues after oral administration, with the highest level in the stomach and the lowest in the brain. In bone marrow cells, the concentration of E28 in all sample points were consistently higher than its half inhibitory concentration against MV4-11 tumour cells.

Keywords:

• E28
• metabolic stability
• CYP phenotyping
• metabolite identification
• tissue distribution
• UHPLC-MS/MS

Disclosure statement

All authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

This work was supported by the Applied Basic Research Program of Sichuan Province under Grant No. 2020YJ0375, and Key Research and Development Projects of Sichuan Province under Grant No. 2021YFS0042.