Imaging mass spectrometry for toxicity assessment: a useful technique to confirm drug distribution in histologically confirmed lesions

Abstract

To evaluate the usefulness of imaging mass spectrometry (IMS) technology for assessing drug toxicity, we analyzed animal tissues in an amiodarone (AMD)-induced phospholipidosis model by IMS and confirmed the relationship between the distribution of AMD, its metabolites, and representative phospholipids (phosphatidylcholine, PC) and histological changes. AMD was administered to rats for 7 days at 150 mg/kg/day. The lung, spleen, and mesenteric lymph node were histologically examined and analyzed using IMS. The detection intensities of AMD, its metabolites, and typical PCs were higher in regions infiltrated by foamy macrophages compared with normal areas. This tendency was common in all three organs analyzed in this study. For the spleen, signals for AMD, its metabolites, and typical PCs were significantly more intense in the marginal zone, where foamy macrophages and vacuolated lymphocytes are abundant, than in the other areas. These results indicate that AMD, its metabolites, and PCs accumulate together in foamy or vacuolated cells, which is consistent with the mechanism of AMD-induced phospholipidosis. They also indicate that IMS is a useful technique for evaluating the distribution of drugs and biological components in the elucidation of toxicity mechanisms.

What is the role of current mass spectrometry in pharmaceutical analysis?

“…A simultaneous analysis of multiple compounds with matrix‐assisted laser desorption ionization (MALDI)‐MSI is demonstrated in a study (Nishidate et al, 2017), where the localization of erlotinib, its metabolites M13 and M14, and heme b was examined in xenograft tissue. Another example is the use of MALDI‐MS in the toxicological study of amiodarone‐induced phospholipidosis in rats which confirms the relationship between the distribution of amiodarone, its metabolites, and representative phospholipids and histological changes (Kashimura et al, 2018). The potential of MSI for studying the CNS drugs crossing the blood‐brain barrier and characterizing the spatial pharmacodynamics and pharmacokinetics has been demonstrated (Liu et al, 2022).…”

Amiodarone, Unlike Dronedarone, Activates Inflammasomes via Its Reactive Metabolites: Implications for Amiodarone Adverse Reactions

“…The fact that the physical properties of dronedarone and amiodarone such as volume of distribution are so different may contribute to the difference in the spectrum of adverse reactions. , Although dronedarone appears to be safer than amiodarone, it can cause adverse reactions including liver injury . Amiodarone also causes liver injury; however, the major serious adverse reaction associated with amiodarone is interstitial lung disease and pulmonary fibrosis. , The histology of amiodarone-induced interstitial lung disease is characterized by foamy macrophages . Amiodarone is concentrated in the same region as these macrophages, and alveolar macrophages are known to have significant CYP3A4 activity .…”

“…Amiodarone also causes liver injury; however, the major serious adverse reaction associated with amiodarone is interstitial lung disease and pulmonary fibrosis. , The histology of amiodarone-induced interstitial lung disease is characterized by foamy macrophages . Amiodarone is concentrated in the same region as these macrophages, and alveolar macrophages are known to have significant CYP3A4 activity . Therefore, bioactivation of amiodarone and inflammasome activation by these macrophages may play an important role in amiodarone-induced interstitial lung disease.…”

The evolving role of investigative toxicology in the pharmaceutical industry

“…Mass spectrometry imaging (MSI) approaches encompass a range of direct ionization methods that sample endogenous and exogenous compounds directly from the surface of tissue sections. Coupled mass spectrometry enables multiplexed label-free spatial analysis of compounds directly from tissue sections and is now being used in drug discovery 53 . Such spatial resolution when coupled to histopathological images has the potential to eliminate bulk analysis artefacts of pathological tissue sampling and focus on adverse biological perturbations at the cellular level 54 .…”