Whole-body tissue distribution study of drugs in neonate mice using desorption electrospray ionization mass spectrometry imaging

Abstract

Although Desorption Electrospray Ionization (DESI) Mass Spectrometry Imaging (MSI) is uniquely suited for whole-body (WB) tissue distribution study of drugs, success in this area has been difficult. Here, we present WB tissue distribution studies using DESI-MSI and a new histological tissue-friendly solvent system. Neonate pups were dosed subcutaneously (SC) with clozapine, compound 1, compound 2, or compound 3. Following euthanization by hypothermia, neonates underwent a transcardiac perfusion (saline) to remove blood. After cryosectioning, DESI-MSI was conducted for the WB tissue slides, followed sequentially by histological staining. Whole-body tissue imaging showed that clozapine and its N-oxide metabolite were distributed in significant amounts in the brain, spinal cord, liver, heart (ventricle), and lungs. Compound 1 was distributed mainly in the liver and muscle, and its mono-oxygenated metabolite was detected by DESI-MSI exclusively in the liver. Compound 2 was distributed mainly in the muscle and fatty tissue. Compound 3 was distributed mainly in fatty tissue and its metabolites were also mainly detected in the same tissue. The results demonstrate the successful application of DESI-MSI in whole-body tissue distribution studies of drugs and metabolites in combination with sequential histology staining for anatomy. The results also identified lipophilicity as the driving force in the tissue distribution of the three Amgen compounds.