Developing safe and efficacious drugs is linked to understanding the complex mechanistic relationships between molecular initiation events of pharmacologically active compounds and the cascade of biological consequences.  Matrix-assisted laser desorption/ionization (MALDI) Imaging Mass Spectrometry (IMS) technology has taken us beyond “plasma centric” studies to directly mapping drug tissue disposition and molecular changes associated with pharmacology and disease pathogenesis. <br/>MALDI IMS correlates analyte tissue distributions with histology images, thereby integrating chemical structures and tissue morphology without the need for labeling techniques.  This emerging technology provides high spatial resolution, sensitivity, and can be quantitative.  Furthermore, MALDI IMS offers the opportunity to further our mechanistic understanding of drug disposition, disease progression and pharmacology (including toxicology) by providing snap shots of temporal and causal changes.  While we have primarily employed MALDI IMS to determine the tissue distribution of drugs and their metabolites, it is becoming evident that more detailed understanding of biological systems can be gained by including the changes in endogenous compound distribution as a function of disease or pharmacology.<br/>This presentation will focus on our efforts to couple MALDI IMS and histology in drug development to better understand tissue disposition and gain mechanistic insights into drug correlated toxicities and efficacy.  Case studies from early and late stage drug development, where MALDI IMS was employed to investigate the mechanisms of adverse events, provide insights into disposition, and PK/PD relationships will be presented.

Molecular visualization of tissues by MALDI imaging MS: Applications in drug discovery and development

256th National Meeting (2018)

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