Metabolomics in Preclinical Drug Safety Assessment

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 4512

Special Issue Editors


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Guest Editor
1. Biochemistry and Molecular Biology Department, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
2. Joint Unit on Experimental Hepatology. University Hospital La Fe (IIS LAFE), 46026 Valencia, Spain
3. CIBEREHD, Instituto de Salud Carlos III, 28029 Madrid, Spain
Interests: DILI, in vitro hepatotoxicity, human hepatocytes gene regulation; drug biotransformation; metabolomics in DILI and hepatotoxicity mechanisms

E-Mail Website
Guest Editor
1. Biochemistry and Molecular Biology Department, Faculty of Medicine, University of Valencia, Valencia, Spain
2. Joint Unit on Experimental Hepatology. University Hospital La Fe (IIS LAFE), 46026 Valencia, Spain
3. CIBEREHD, Instituto de Salud Carlos III, 28029 Madrid, Spain
Interests: metabolomics; lipidomics; drug toxicity; liver diseases; steatosis

Special Issue Information

Dear Colleagues,

The assessment of the potential toxicity of a new drug is critical during early phases of drug development as well in post-marketing surveillance. Investigation into the molecular events by which a drug causes injury is of utmost importance to improve drug safety. Metabolomics, a rapidly growing 'omic' that examines global changes in metabolite composition in cells and tissues, is a powerful tool that can be used to describe alterations caused by a drug in cells or tissues and to uncover its pathophysiological significance. Recent analytical and data analysis tools have made it possible and feasible to monitor metabolic alterations and cells’ responses to an injuring agent over a wide range of cells’ metabolites. On the basis of such analyses, it is possible to investigate global metabolome responses, discover altered outcome pathways, and uncover the mechanisms of toxicity involved to date. Based on the magnitude and relevance of metabolome changes induced in cells, tissues, or in vivo, it is also possible to discriminate between toxic and non-toxic compounds/concentrations. Toxicometabolomics analysis is the most closely related strategy to classical knowledge of disturbed biochemical pathways. It allows for the rapid identification of the potential targets of a hazardous compound and can also assist in the identification of potential toxic candidates in the early phases of drug discovery.

This Special Issue of Metabolites, entitled “Metabolomics in preclinical drug safety assessment”, aims to present the scope and applications of metabolomics in the early assessment of drug safety in the first stages of drug development, gathering  cutting-edge studies that explore and exemplify the use of metabolomics in different toxicological areas in vitro and in vivo. The issue is structured under several subheadings: Part A: general principles of metabolomic analysis and its application in drug safety assessment; Part B: metabolomics drug safety assessment in in vitro studies; Part C: in vivo metabolomic studies on drug safety; Part D: data quality assurance; Part E: metabolomic data analysis; and Part F: metabolomic data acceptance in the regulatory process.

We encourage the submission of original articles and reviews focused on these different subheadings and  addressing the following topics:

  • General principles of metabolomics analysis for drug safety evaluation;
  • Novel instrumental approaches in metabolomics analysis in early drug discovery;
  • Metabolomics analysis in preclinical hepatotoxicity studies in vitro and in vivo;
  • Metabolomics analysis in preclinical renal toxicity studies in vitro and in vivo;
  • Metabolomics analysis in preclinical hematopoietic system toxicity studies in vitro and in vivo;
  • Metabolomics analysis in preclinical neural toxicity studies in vitro and in vivo;
  • Metabolomics analysis in preclinical cardiac toxicity studies  in vitro and in vivo;
  • Quality assurance and GLPs in metabolomics;
  • Metabolomics data analysis and metabolic pathways;
  • General criteria for metabolomics data acceptance by drug regulatory agencies.

Articles may also address toxicity biomarker identification, metabolomics approaches to unraveling toxicity mechanisms and altered outcome pathways (AOPs), as well the development of prediction models for drug-induced toxicity.

Dr. José V. Castell
Dr. Marta Moreno-Torres
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolomics
  • toxicometabolomics
  • lipidomics
  • preclinical toxicology
  • preclinical drug safety
  • drug discovery
  • biomarker discovery
  • liver, kidney
  • cardiac
  • neural
  • hematopoietic metabolomics

Published Papers (3 papers)

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Research

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12 pages, 2356 KiB  
Article
Thyroid Hormone Metabolites Quantified in Pup and Adult Rat Cerebellum, Cortex and Whole-Brain Samples Using an Automated Online SPE-LC-MS/MS Method
by Christiane Hindrichs, Tilmann Walk, Robert Landsiedel, Hennicke Kamp, Steffen Schneider, Stephanie Melching-Kollmuss and Dorothee Funk-Weyer
Metabolites 2024, 14(1), 61; https://doi.org/10.3390/metabo14010061 - 17 Jan 2024
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Abstract
Changes in thyroid hormone (TH) levels in rat brain at early developmental stages are correlated with adverse effects on offspring development. To characterize the ability of substances to interfere with the TH concentrations in, e.g., rat brain, it is essential to know the [...] Read more.
Changes in thyroid hormone (TH) levels in rat brain at early developmental stages are correlated with adverse effects on offspring development. To characterize the ability of substances to interfere with the TH concentrations in, e.g., rat brain, it is essential to know the mean TH concentrations in this tissue under control conditions. In this publication, an online solid-phase extraction (SPE) liquid chromatography (LC) tandem mass spectrometry (MS/MS) method was validated and used to measure TH metabolites (T4, T3, rT3, T2 and T1) in the brains of untreated rats. Data on TH concentrations in the whole brain and separate data from the cerebellum and the cortex are shown. The corresponding samples were gathered from young rats at postnatal days (PND) 4 and 21/22 and from adult rats. The results show inter alia the high accuracy and precision of the method, and LOQs of 0.02 ng/mL were determined for T1, T2 and rT3 and of 0.15 ng/mL for T3 and T4. Technical variability is low, as shown by the relative standard deviations of 7.5–20%. For our rat model, we found that T4, T3 and T2 concentrations rise from PND4 to PND21, whereas the rT3 concentration decreases; as well as there is no statistical difference between TH concentrations in the male and female rat brain. This method is suitable to analyze TH metabolites in the brain and build up a database of historical TH concentrations in control rats. Together, this yields a robust diagnostic tool to detect potentially adverse disturbances of TH homeostasis in the most vulnerable anatomic structure. Full article
(This article belongs to the Special Issue Metabolomics in Preclinical Drug Safety Assessment)
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15 pages, 3524 KiB  
Article
Predicting Valproate-Induced Liver Injury Using Metabolomic Analysis of Ex Ovo Chick Embryo Allantoic Fluid
by Vanessa Tagliatti, Caroline Descamps, Margaux Lefèvre and Jean-Marie Colet
Metabolites 2023, 13(6), 721; https://doi.org/10.3390/metabo13060721 - 2 Jun 2023
Cited by 1 | Viewed by 1216
Abstract
The use of sensitive animals in toxicological studies tends to be limited. Even though cell culture is an attractive alternative, it has some limitations. Therefore, we investigated the potential of the metabolomic profiling of the allantoic fluid (AF) from ex ovo chick embryos [...] Read more.
The use of sensitive animals in toxicological studies tends to be limited. Even though cell culture is an attractive alternative, it has some limitations. Therefore, we investigated the potential of the metabolomic profiling of the allantoic fluid (AF) from ex ovo chick embryos to predict the hepatotoxicity of valproate (VPA). To this end, the metabolic changes occurring during embryo development and following exposure to VPA were assessed using 1H-NMR spectroscopy. During embryonic development, our findings indicated a metabolism progressively moving from anaerobic to aerobic, mainly based on lipids as the energy source. Next, liver histopathology of VPA-exposed embryos revealed abundant microvesicles indicative of steatosis and was metabolically confirmed via the determination of lipid accumulation in AF. VPA-induced hepatotoxicity was further demonstrated by (i) lower glutamine levels, precursors of glutathione, and decreased β-hydroxybutyrate, an endogenous antioxidant; (ii) changes in lysine levels, a precursor of carnitine, which is essential in the transport of fatty acids to the mitochondria and whose synthesis is known to be reduced by VPA; and (iii) choline accumulation that promotes the export of hepatic triglycerides. In conclusion, our results support the use of the ex ovo chick embryo model combined with the metabolomic assessment of AF to rapidly predict drug-induced hepatotoxicity. Full article
(This article belongs to the Special Issue Metabolomics in Preclinical Drug Safety Assessment)
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Review

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16 pages, 2331 KiB  
Review
Metabolomics in Preclinical Drug Safety Assessment: Current Status and Future Trends
by Fenna Sillé and Thomas Hartung
Metabolites 2024, 14(2), 98; https://doi.org/10.3390/metabo14020098 - 31 Jan 2024
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Abstract
Metabolomics is emerging as a powerful systems biology approach for improving preclinical drug safety assessment. This review discusses current applications and future trends of metabolomics in toxicology and drug development. Metabolomics can elucidate adverse outcome pathways by detecting endogenous biochemical alterations underlying toxicity [...] Read more.
Metabolomics is emerging as a powerful systems biology approach for improving preclinical drug safety assessment. This review discusses current applications and future trends of metabolomics in toxicology and drug development. Metabolomics can elucidate adverse outcome pathways by detecting endogenous biochemical alterations underlying toxicity mechanisms. Furthermore, metabolomics enables better characterization of human environmental exposures and their influence on disease pathogenesis. Metabolomics approaches are being increasingly incorporated into toxicology studies and safety pharmacology evaluations to gain mechanistic insights and identify early biomarkers of toxicity. However, realizing the full potential of metabolomics in regulatory decision making requires a robust demonstration of reliability through quality assurance practices, reference materials, and interlaboratory studies. Overall, metabolomics shows great promise in strengthening the mechanistic understanding of toxicity, enhancing routine safety screening, and transforming exposure and risk assessment paradigms. Integration of metabolomics with computational, in vitro, and personalized medicine innovations will shape future applications in predictive toxicology. Full article
(This article belongs to the Special Issue Metabolomics in Preclinical Drug Safety Assessment)
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