Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis

Abstract

Knowledge about the region-specific absorption profiles from the gastrointestinal tract of orally administered drugs is a critical factor guiding dosage form selection in drug development. We have used a novel approach to study three well-characterized permeability and absorption marker drugs in the intestine. Propranolol and metoprolol (highly permeable compounds) and atenolol (low-moderate permeability compound) were orally co-administered to rats. The site of drug absorption was revealed by high spatial resolution matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and complemented by quantitative measurement of drug concentration in tissue homogenates. MALDI-MSI identified endogenous molecular markers that illustrated the villi structures and confirmed the different absorption sites assigned to histological landmarks for the three drugs. Propranolol and metoprolol showed a rapid absorption and shorter transit distance in contrast to atenolol, which was absorbed more slowly from more distal sites. This study provides novel insights into site specific absorption for each of the compounds along the crypt-villus axis, as well as confirming a proximal-distal absorption gradient along the intestine. The combined analytical approach allowed the quantification and spatial resolution of drug distribution in the intestine and provided experimental evidence for the suggested absorption behaviour of low and highly permeable compounds.

Detection and Visualization of Food-derived Polyphenols by Matrix-assisted Laser Desorption/Ionization Mass Spectrometry Imaging

“…The intestinal absorption behaviors of propranolol and metoprolol (high-permeability compounds) and atenolol (a lowpermeability compound) were evaluated by MALDI-MS imaging. (20) The results provided novel insight into site-specific absorption along the crypt-villus axis for each of the compounds, and confirmed a proximal-distal absorption gradient along the intestine. (20) In a tuberculosis research study, several anti-tuberculosis drugs including rifampicin, pyrazinamide, and moxifloxacin were administered to patients, and MALDI-MS imaging was used to visualize the distribution of these drugs in tuberculosis lesions.…”

“…(20) The results provided novel insight into site-specific absorption along the crypt-villus axis for each of the compounds, and confirmed a proximal-distal absorption gradient along the intestine. (20) In a tuberculosis research study, several anti-tuberculosis drugs including rifampicin, pyrazinamide, and moxifloxacin were administered to patients, and MALDI-MS imaging was used to visualize the distribution of these drugs in tuberculosis lesions. (27) The results revealed that rifampicin and pyrazinamide efficiently penetrated the tuberculosis infection sites in lung lesions but did not diffuse well in caseum.…”

“…(17)(18)(19) Currently, the development of MALDI-MS-aided imaging is receiving considerable attention since it not only provides information on the presence of compounds, but can also be used to visualize their distribution and/or localization in biological tissues, overcoming the limitations of LC-MS methods. (14,20,21) The combination of MS detection with spatial localization presents a novel scientific methodology for food and drug development fields. (14,22) Numerous reports on the application of MALDI-MS imaging to the visualization of a wide mass range of peptides, (23) proteins, (24,25) lipids, (26) drugs, (27)(28)(29) and food compounds (30) have been published.…”

Yale School of Public Health Symposium on tissue imaging mass spectrometry: illuminating phenotypic heterogeneity and drug disposition at the molecular level

“…It provides insights into the biodistribution of compounds, while simultaneously generating data on pharmacodynamic biomarkers. Dr. Goodwin presented data from AZ that showed how the use of a range of multimodal imaging techniques improves understanding about compound efficacy, safety, and targeted drug delivery [ 32 , 33 ]. Investigating histopathological-targeted drug-induced toxicity is now readily achieved using high-spatial resolution and high-mass resolution IMS.…”

Physiologically Relevant, Humanized Intestinal Systems to Study Metabolism and Transport of Small Molecule Therapeutics

“…Absorption (F a ) is a combination of solubility and permeability and can be predicted with confidence in humans (Artursson and Karlsson, 1991;Fagerholm, 2007;Wei et al, 2009) and rats (Nilsson et al, 2017). In contrast, discrete measurement of F g , in vitro, has not been reported due to the lack of reliable assays derived from human intestinal sections.…”