The Role of Metabonomics at the Interface Between Drug Metabolism and Safety Assessment

Nigel      J. Waters

doi:10.2174/138920010794233512

Abstract

Safety assessment of candidate drugs is a key stage in drug development and one which represents a significant attritional hurdle. There is also a focused effort in drug metabolism studies to assess bioactivation potential based on the notion this could lead to the risk of macromolecule adduct formation and subsequent toxicological consequences. However, characterization of the molecular mechanisms of drug toxicity still remains an enormous challenge. Recent advancements in ‘omics sciences, and in particular metabonomics, has enabled some elucidation or insights into toxicological sequelae. Metabonomics is a global metabolic profiling framework which utilizes high resolution analytics (typically NMR and mass spectrometry) together with chemometric statistical tools (such as principal component analysis and partial least squares) to derive an integrated picture of both endogenous and xenobiotic metabolism. This review details some of the current progress in the application of metabonomics in drug safety and metabolism.

Keywords: Bioactivation, biomarkers, covalent binding, drug discovery, metabolic profiling, metabolomics, pharmacokinetics, toxicology, NMR, mass spectrometry, principal compo-nent analysis, partial least squares, idiosyncratic toxicities, DMPK, DEREK, METEOR, quinones, epox-ides, nitrenium ions, alkyl halides, Michael acceptors, GSH adducts, semicarbazide, methoxylamine, hepatotoxins, non-hepatotoxins, Metabonomics, chemometric analysis, PCA, PLS, HPLC technol-ogy (e.g., ultra high performance liquid chromatography or UHPLC), GC, CE, principal components analysis (PCA), PLS-DA, vehicle control, treatment 1, treatment 2, DILI, phospholipase A2 pathway, arachidonic acid, uteroglobin, phosphatidylcholine, phos-phatidylinositol, adenosylmethionine, p-cresol, sulfotransferase isoform, peroxisome proliferator-activated receptor R (PPARR), fenofibrate, medium chain dicarboxylic acids (MCDAs), 1-cyano-2-hydroxy-3-butene (CHB), Statistical TOtal Correlation SpectroscopY (STOCSY)