Metabonomics in preclinical drug development

Metabonomics has emerged as a key technology in preclinical drug discovery and development. The technology enables noninvasive systems assessment of untoward effects induced by candidate compounds characterising a broad spectrum of biological responses on an individual animal basis in a relatively rapid-throughput fashion, thus making it an ideal addition to early preclinical safety assessment. However, the implementation and interpretation of the technology and data it generates is not something that should be trivialised. Proper expertise in biological sciences, analytical sciences (nuclear magnetic resonance and/or mass spectrometry) and chemometrics should all be considered necessary prerequisites. If these factors are properly considered, the technology can add significant value as a tool for preclinical toxicologists.

[1]  E. Verheij,et al.  The role of mass spectrometry in systems biology : data processing and identification strategies in metabolomics , 2004 .

[2]  Donald G Robertson,et al.  Metabonomics in toxicology: a review. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[3]  Iain Beattie,et al.  Ultra-performance liquid chromatography coupled to quadrupole-orthogonal time-of-flight mass spectrometry. , 2004, Rapid communications in mass spectrometry : RCM.

[4]  M. Reily,et al.  In vivo toxicity screening programs using metabonomics. , 2002, Combinatorial chemistry & high throughput screening.

[5]  John C. Lindon,et al.  Toxicological applications of magnetic resonance , 2004 .

[6]  John A Bilello,et al.  The agony and ecstasy of "OMIC" technologies in drug development. , 2005, Current molecular medicine.

[7]  Julian L Griffin,et al.  Metabonomics: NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterisation of xenobiotic toxicity and disease diagnosis. , 2003, Current opinion in chemical biology.

[8]  M. Reily,et al.  Effect of dexamethasone on the metabonomics profile associated with phosphodiesterase inhibitor-induced vascular lesions in rats. , 2002, Toxicology and applied pharmacology.

[9]  M. Hodson,et al.  Development of a multivariate statistical model to predict peroxisome proliferation in the rat, based on urinary 1H-NMR spectral patterns , 2004, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[10]  John C. Lindon,et al.  NMR Spectroscopy: Principles and Instrumentation , 2005 .

[11]  Svante Wold,et al.  Modelling and diagnostics of batch processes and analogous kinetic experiments , 1998 .

[12]  J. Lindon,et al.  Metabonomics: a platform for studying drug toxicity and gene function , 2002, Nature Reviews Drug Discovery.

[13]  M. Barker,et al.  Partial least squares for discrimination , 2003 .

[14]  J C Lindon,et al.  Directly coupled HPLC-NMR and HPLC-NMR-MS in pharmaceutical research and development. , 2000, Journal of chromatography. B, Biomedical sciences and applications.

[15]  John C. Lindon,et al.  Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status , 2004, Archives of Toxicology.

[16]  John C. Lindon,et al.  NMR Spectroscopy of Biofluids , 1999 .

[17]  Jan van der Greef,et al.  Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis. , 2004, International immunopharmacology.

[18]  Andrew W Nicholls Jeremy K Nicholson John N Haseld A metabonomic approach to the investigation of drug-induced phospholipidosis: an NMR spectroscopy and pattern recognition study. , 2000, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[19]  D. Kell,et al.  Metabolomics by numbers: acquiring and understanding global metabolite data. , 2004, Trends in biotechnology.

[20]  T. L. James,et al.  CHAPTER 2 – PRINCIPLES OF NUCLEAR MAGNETIC RESONANCE , 1975 .

[21]  I. Wilson,et al.  An NMR‐based metabonomic approach to investigate the biochemical consequences of genetic strain differences: application to the C57BL10J and Alpk:ApfCD mouse , 2000, FEBS letters.

[22]  E Holmes,et al.  Metabonomic investigations into hydrazine toxicity in the rat. , 2001, Chemical research in toxicology.

[23]  Oliver Fiehn,et al.  Combining Genomics, Metabolome Analysis, and Biochemical Modelling to Understand Metabolic Networks , 2001, Comparative and functional genomics.

[24]  Ad Bax,et al.  Improved solvent suppression in one-and two-dimensional NMR spectra by convolution of time-domain data , 1989 .

[25]  Timothy M. D. Ebbels,et al.  Statistical experimental design and partial least squares regression analysis of biofluid metabonomic nmr and clinical chemistry data for screening of adverse drug effects , 2004 .

[26]  J. Lindon,et al.  'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[27]  P J Sadler,et al.  Use of high-resolution proton nuclear magnetic resonance spectroscopy for rapid multi-component analysis of urine. , 1984, Clinical chemistry.

[28]  S. Wold,et al.  Source contributions to ambient aerosol calculated by discriminat partial least squares regression (PLS) , 1988 .

[29]  J. Nicholson,et al.  Investigations into the biochemical effects of region-specific nephrotoxins. , 1989, Molecular pharmacology.

[30]  Daniel Raftery,et al.  Use of selective TOCSY NMR experiments for quantifying minor components in complex mixtures: application to the metabonomics of amino acids in honey. , 2005, Analytical chemistry.

[31]  John C Lindon,et al.  Integrated application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse. , 2004, Journal of pharmaceutical and biomedical analysis.

[32]  G. Kruppa,et al.  Metabolomics applications of FT-ICR mass spectrometry. , 2005, Mass spectrometry reviews.

[33]  Henrik Antti,et al.  Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. , 2003, Toxicology and applied pharmacology.

[34]  E Holmes,et al.  Investigations into biochemical changes due to diurnal variation and estrus cycle in female rats using high-resolution (1)H NMR spectroscopy of urine and pattern recognition. , 2001, Analytical biochemistry.

[35]  P J Sadler,et al.  High resolution 1H n.m.r. studies of vertebrate blood and plasma. , 1983, The Biochemical journal.

[36]  Svante Wold,et al.  Pattern recognition by means of disjoint principal components models , 1976, Pattern Recognit..

[37]  J. van der Greef,et al.  Partial linear fit: A new NMR spectroscopy preprocessing tool for pattern recognition applications , 1996 .

[38]  G. Stephanopoulos,et al.  Systematic quantification of complex metabolic flux networks using stable isotopes and mass spectrometry. , 2003, European journal of biochemistry.

[39]  Brian C Sweatman,et al.  Effects of feeding and body weight loss on the 1H-NMR-based urine metabolic profiles of male Wistar Han Rats: Implications for biomarker discovery , 2004, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[40]  T. Ebbels,et al.  Geometric trajectory analysis of metabolic responses to toxicity can define treatment specific profiles. , 2004, Chemical research in toxicology.

[41]  M. Reily,et al.  Metabonomic assessment of vasculitis in rats , 2007, Cardiovascular Toxicology.

[42]  G. Bodenhausen,et al.  Principles of nuclear magnetic resonance in one and two dimensions , 1987 .

[43]  M. Reily,et al.  Metabonomics: evaluation of nuclear magnetic resonance (NMR) and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[44]  Elaine Holmes,et al.  NMR-based metabonomic studies on the biochemical effects of commonly used drug carrier vehicles in the rat. , 2002, Chemical research in toxicology.

[45]  Stephanie Ringeissen,et al.  Potential urinary and plasma biomarkers of peroxisome proliferation in the rat: identification of N-methylnicotinamide and N-methyl-4-pyridone-3-carboxamide by 1H nuclear magnetic resonance and high performance liquid chromatography , 2003, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[46]  G. Harrigan Metabolic profiling: pathways in drug discovery. , 2002, Drug discovery today.

[47]  Elaine Holmes,et al.  Metabonomic applications in toxicity screening and disease diagnosis. , 2002, Current topics in medicinal chemistry.

[48]  D. Baunsgaard,et al.  Combination of ‘omics’ data to investigate the mechanism(s) of hydrazine-induced hepatotoxicity in Rats and to identify potential biomarkers , 2004, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[49]  T. Ebbels,et al.  Analytical reproducibility in (1)H NMR-based metabonomic urinalysis. , 2002, Chemical research in toxicology.

[50]  J. Trygg,et al.  Evaluation of the orthogonal projection on latent structure model limitations caused by chemical shift variability and improved visualization of biomarker changes in 1H NMR spectroscopic metabonomic studies. , 2005, Analytical chemistry.

[51]  Jeremy K Nicholson,et al.  Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity. , 2004, Chemical research in toxicology.

[52]  A. Fernie,et al.  Metabolite profiling: from diagnostics to systems biology , 2004, Nature Reviews Molecular Cell Biology.

[53]  J. Lindon,et al.  An hypothesis for a mechanism underlying hepatotoxin-induced hypercreatinuria , 2003, Archives of Toxicology.

[54]  Timothy M. D. Ebbels,et al.  Batch statistical processing of 1H NMR‐derived urinary spectral data , 2002 .

[55]  Elaine Holmes,et al.  Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis , 2004, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.