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Whole-body spatially-resolved metabolomics method for profiling the metabolic differences of epimer drug candidates using ambient mass spectrometry imaging

Author:
Luo, Zhigang, Liu, Dan, Pang, Xuechao, Yang, Wanqi, He, Jiuming, Zhang, Ruiping, Zhu, Chenggen, Chen, Yanhua, Li, Xin, Zhang, Jianjun, Shi, Jiangong, Abliz, Zeper
Source:
Talanta 2019 v.202 pp. 198-206
ISSN:
0039-9140
Subject:
air, brain, computer software, desorption, drugs, gamma-aminobutyric acid, image analysis, ionization, ions, mass spectrometry, metabolites, metabolomics, neurotransmitters, oral administration, pharmacodynamics, rats, spectrometers, stomach
Abstract:
Investigation of the in vivo drug action and metabolic differences of epimer drugs is challenging. Whole-body MSI analysis can visually present the stereoscopic distribution of molecules related to the interaction of drugs and organisms, and can provide more comprehensive organ-specific profiling information. Herein, we developed a whole-body spatially-resolved imaging metabolomics method based on an air flow-assisted ionisation desorption electrospray ionisation (AFADESI)-MSI system coupled with a high-resolution mass spectrometer and highly discriminating imaging software. The epimeric sedative-hypnotic drug candidates YZG-331 and YZG-330 were selected as examples, and rats administered normal or high oral doses were used. By performing multivariate statistical data-mining on the combined MSI data, organ-specific differential ions were screened. By comparing the variations in the relative contents of the drugs, their metabolites, and endogenous neurotransmitters throughout whole-body tissue sections of the rats, rich information that could potentially explain the more significant sedative-hypnotic effects of YZG-330 compared to YZG-331 was obtained. Such as the increased ratio of gamma-aminobutyric acid in the brain and stomach of the rats (0.25, 0.47, 0.68, 0.30, and 0.89 for the control and YZG-331-H, YZG-330-H, YZG-331-L, and YZG-330-L, respectively) were interesting. This study provided a convenient and visual method to investigate in vivo molecular metabolic differences and provide insight towards a better understanding of the pharmacodynamic mechanisms of these sedative-hypnotic drug-candidates.
Agid:
6392823