Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration

Groseclose, M. Reid; Laffan, Susan; Frazier, Kendall S.; Hughes‐Earle, Angela; Castellino, Stephen

doi:10.1007/s13361-015-1103-4

Cited by 48 publications

(40 citation statements)

References 25 publications

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“…We previously developed a novel quantitative IMS method for small molecule drugs, making it possible to normalize ion suppression of a drug in some tissues using internal standards such as stable isotope labeling and structural analogs 32 . The quantitative capability of MALDI-IMS has recently been recognized and used in several studies applying quantitative IMS to drug discovery research 37 , 38 . The concentrations of epertinib in brain metastasis of both IVMs were comparable.…”

Section: Discussionmentioning

confidence: 99%

Distribution analysis of epertinib in brain metastasis of HER2-positive breast cancer by imaging mass spectrometry and prospect for antitumor activity

Tanaka

Hirata

Shinonome

et al. 2018

Sci Rep

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Epertinib (S-222611) is a potent, reversible, and selective tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), human EGFR2 (HER2), and human EGFR4. We developed experimental brain metastasis models by intraventricular injection (intraventricular injection mouse model; IVM) of HER2-positive breast cancer (MDA-MB-361-luc-BR2/BR3) or T790M-EGFR-positive lung cancer (NCI-H1975-luc) cells. After a single oral administration, epertinib and lapatinib concentrations in brain metastatic regions were analyzed by quantitative imaging mass spectrometry. In the NCI-H1975 lung cancer IVM, the concentration of epertinib in brain metastasis was comparable to that of lapatinib. However, in the MDA-MB-361 breast cancer IVM, the concentration of epertinib in brain metastasis was >10 times higher than that of lapatinib. Furthermore, the epertinib tumor-to-normal brain ratio was ~4 times higher than that of lapatinib. Blood-tumor barrier (BTB) permeability was assessed in each brain metastatic region. In the lung cancer model, fluorescently labeled dextran was more highly detected in brain metastatic regions than in brain parenchyma. However, in breast cancer models, dextran fluorescence intensity in brain metastatic regions and brain parenchyma were comparable, suggesting that the BTB remained largely intact. Epertinib would be promised as a therapeutic agent for HER2-positive breast cancer with brain metastasis.

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Section: Discussionmentioning

confidence: 99%

Distribution analysis of epertinib in brain metastasis of HER2-positive breast cancer by imaging mass spectrometry and prospect for antitumor activity

Tanaka

Hirata

Shinonome

et al. 2018

Sci Rep

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“…This approach is effective but relies generally on the analysis of tissue homogenates or biological fluids that leads to the loss of analyte localization. IMS can conserve this information without the need for complex sample preparation [40]. …”

Section: Investigation Of Mechanisms Of Toxicitymentioning

confidence: 99%

Potential of MALDI imaging for the toxicological evaluation of environmental pollutants

Lagarrigue

Caprioli

Pineau

2016

Journal of Proteomics

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Risk assessment related to the exposure of humans to chemicals released into the environment is a major concern of our modern societies. In this context, toxicology plays a crucial role to characterize the effects of this exposure on health and identify the targets of these molecules. MALDI imaging mass spectrometry (IMS) is an enabling technology for biodistribution studies of chemicals. Although the majority of published studies are presented in a pharmacological context, the concepts discussed in this review can be applied to the toxicological evaluation of chemicals released into the environment. The major asset of IMS is the simultaneous localization and identification of a parent molecule and its metabolites without labeling and without any prior knowledge. Quantification methods developed in IMS are presented with application to an environmental pollutant. IMS is effective in the localization of chemicals and endogenous species. This opens unique perspectives for the discovery of molecular alterations in metabolites and protein biomarkers that could help for a better understanding of toxicity mechanisms. Distribution studies of agrochemicals in plants by IMS can contribute to a better understanding of their mode of action and to a more effective use of these chemicals, avoiding the current concern of environmental damage.

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“…Better understanding of these factors is needed to improve prediction of the ADME characteristics of drugs and chemicals administered to neonates. There are numerous examples of drugs that behave quite differently in adults and neonates that can be explained by the lack of maturation of various transporters or metabolic enzymes such as propofol, pazopanib, or dabrafenib, among many others (Groseclose et al, 2015;Frazier, 2017;Michelet et al, 2018;Frazier et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Ontogeny and Cross-species Comparison of Pathways Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Neonates (Review): Kidney

et al. 2020

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The kidneys play an important role in many processes, including urine formation, water conservation, acid-base equilibrium, and elimination of waste. The anatomic and functional development of the kidney has different maturation time points in humans versus animals, with critical differences between species in maturation before and after birth. Absorption, distribution, metabolism, and excretion (ADME) of drugs vary depending on age and maturation, which will lead to differences in toxicity and efficacy. When neonate/ juvenile laboratory animal studies are designed, a thorough knowledge of the differences in kidney development between newborns/ children and laboratory animals is essential. The human and laboratory animal data must be combined to obtain a more complete picture of the development in the kidneys around the neonatal period and the complexity of ADME in newborns and children. This review examines the ontogeny and cross-species differences in ADME processes in the developing kidney in preterm and term laboratory animals and children. It provides an overview of insights into ADME functionality in the kidney by identifying what is currently known and which gaps still exist. Currently important renal function properties such as glomerular filtration rate, renal blood flow, and ability to concentrate are generally well known, while detailed knowledge about transporter and metabolism maturation is growing but is still lacking. Preclinical data in those properties is limited to rodents and generally covers only the expression levels of transporter or enzyme-encoding genes. More knowledge on a functional level is needed to predict the kinetics and toxicity in neonate/juvenile toxicity and efficacy studies. SIGNIFICANCE STATEMENTThis review provides insight in cross-species developmental differences of absorption, distribution, metabolism, and excretion properties in the kidney, which should be considered in neonate/juvenile study interpretation, hypotheses generation, and experimental design.dependent on the specialized subcellular structural and functional properties of renal tubule epithelium, including their various transporters, metabolic activity, and membrane integrity. Therefore, the development and maturation of these processes in pediatric patients or in animals can have a profound effect on the disposition and fate of administered drug therapies that depend on the kidney for filtration, uptake, secretion, and/or metabolism.

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Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration

Cited by 48 publications

References 25 publications

Distribution analysis of epertinib in brain metastasis of HER2-positive breast cancer by imaging mass spectrometry and prospect for antitumor activity

Distribution analysis of epertinib in brain metastasis of HER2-positive breast cancer by imaging mass spectrometry and prospect for antitumor activity

Potential of MALDI imaging for the toxicological evaluation of environmental pollutants

Ontogeny and Cross-species Comparison of Pathways Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Neonates (Review): Kidney

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