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European Biopharmaceutical Review

Rising to the Challenge: Metabolomics in Disease and Drug Development

Steven Fischer at Agilent Technologies describes the pitfalls associated with metabolomics research and the new tools developed to overcome them

Metabolomics is a developing analytical approach that is rapidly growing in importance as a tool to improve the diagnosis and treatment of disease, as well as to speed up the drug development process. Unlike genomics or proteomics, which only reveal part of what might be happening in a cell, metabolomic profiling can give an instantaneous snapshot of the entire physiology of that cell. In drug development, most pharmaceutical companies are constantly searching for ways to speed up this process and to reduce cost. This means that problems with compounds that would make unsuitable drug candidates should be identified as quickly as possible.

The objective is to find those few molecules that have the right biochemical properties to become the next blockbuster drug by sifting through the failures to find the few successes. Efficacy and toxicology are important issues in getting a drug to market. Metabolomics can be used to discover biomarkers to track drug efficacy or uncover potential toxic side effects in lead compounds at the molecular level.

SEPARATION CHALLENGES FOR METABOLOMICS

Separation is an important part of metabolomics because the samples are complex. The chemical information in the retention or migration time of the separation is used to track and identify a metabolite undergoing analysis. This is necessary because mass spectrometry (MS) alone cannot distinguish isobaric metabolites, whereas chromatography can be used to separate and identify isomers. The two most commonly used separation techniques are gas chromatography (GC) and liquid chromatography (LC).

Gas chromatography and mass spectrometry (GC/MS) is an effective combination for the analysis of volatile chemicals. Metabolites, therefore, must be volatile or amenable to chemical derivatisation to render them volatile to be analysed by GC/MS. Certain types of samples are particularly well suited to GC/MS analyses (see Figure 1). These include plant terpenes and essential oils, which are volatile and do not ionise well by liquid chromatography/mass spectrometry (LC/MS) techniques.

Other analytes generally compatible with GC/MS include steroids, diglycerides, mono-, di- and trisaccharides, and sugar alcohols. Liquid chromatography can separate metabolites that are not volatile without derivatisation. As a result, LC/MS can analyse a much wider range of chemical species


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Steven Fischer studied Chemistry at California State University, Hayward. In 1986, he joined Agilent Technologies in Santa Clara (previously part of Hewlett-Packard Company), where he has designed and applied HPLC/MS instrumentation for analytical problems for 16 years. He has over 40 issued patents in the field of mass spectrometry. Recently, he has focused his attention on the challenges of metabolomics analysis and is currently a Senior Applications Chemist for Metabolomics, actively developing solutions for metabolomics using mass spectrometry.
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Steven Fischer
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