Emerging Safety Science Workshop Summary (2008) / Chapter Skim
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5 Screening Technologies III: Metabolomics
5 Screening Technologies III: Metabolomics
Pages 50-58
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From page 50... ...
The presentations addressing metabolomics illustrated how the technology is being used to gather information on toxicities and their underlying mechanisms. They highlighted four categories of metabolites that can provide insights at varying levels of complexity: • Markers for the activities of single enzymes • Direct multiparametric markers, which can indicate lipid elevation or lowering, metabolic control, insulin sensitivity, or inflammation • Multiparametric surrogate markers, which offer details about questions that are difficult to analyze directly, such as gluconeogenesis/ glycolysis, oxidative stress, and tissue damage and apoptosis • Mode-of-action markers, which indicate the presence of such responses as lipid signaling and regulatory metabolites 50
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From page 51... ...
Metabolon has developed proprietary software that makes it possible to identify automatically all the ions that are scanned by the spectrometers. Using automated processing techniques based on the biological variation of the compounds within samples, the researchers are able to reconstruct the original molecules to which the ions belonged before going through the system.
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From page 52... ...
The first is a study carried out with Bristol-Myers Squibb researchers who were interested in different HIV protease inhibitors, many of which have a side effect of lipidystrophy, a degenerative condition in the body's adipose tis
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From page 53... ...
The scatter plots of the different HIV protease inhibitors display very different levels of perturbation. The earlier protease inhibitors, such as lopinavir and nelfinavir, tend to show much more overall biochemical perturbation, while the newer ones show less.
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From page 54... ...
Earlier protease inhibitors, such as lopinavir and nelfinavir, show more overall biochemical perturbation, while the newer protease inhibitors show less. 5-2 Atazanavir caused the least amount of perturbation and was most similar to the vehicle control group.
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From page 55... ...
The Biocrates Process The technology platforms used by Biocrates and Metabolon are similar. The Biocrates platform provides fully automated sample preparation, mass spectrometric identification, and quantitation; bioinformatics is used for technical validations, visualization of statistics, and biochemical interpretation; and the entire process is based on an in-house bio bank or on samples collected from the partners with which Biocrates works.
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From page 56... ...
Pharmaceutical applications include studies of drug metabolism and pharmacokinetics, safety and toxicology, and pharmacodynamics and efficacy. Four categories of metabolites have been established, all of which offer insights at differing levels of complexity: • Biomarkers for the activities of single enzymes, which are relatively straightforward, as a simple ratio of product concentration to substrate concentration will generally provide an idea of the quantitative activity of a single enzyme • Direct multiparametric markers, or groups of markers that can indicate lipid elevation or lowering, metabolic control, insulin sensitivity, or inflammation • Multiparametric surrogate markers, or groups of markers that offer details about questions that are difficult to analyze directly, such as gluconeogenesis/glycolysis, oxidative stress, and tissue damage and apoptosis • Mode-of-action markers, or markers that indicate the presence of such responses as lipid signaling and regulatory metabolites An Example To illustrate the utility of metabolomics, Weinerger described a study of puromycin-induced toxicity.
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From page 57... ...
The analysis did, however, identify a number of markers for a wide variety of kidney-specific outcomes and mechanisms. It identified markers for • moderate polyuria and, in at least half a dozen compound classes, tubular dysfunction; • general inflammation and oxidative stress, such as dose-dependent activation of COX, 12-LOX, and 15-LOX, although there was no sign of systemic oxidative stress; and • time-dependent moderate ketosis and the de-repression of NO synthase.
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From page 58... ...
Further, he suggested that throughout the pharmaceutical industry, pharmacology, preclinical, clinical, and toxicology departments should focus on the same question of drug reaction utilizing all available perspectives. Such unification of disciplines could help reinforce evidence-based drug development.
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