Toxicogenomics – A Drug Development Perspective - Genomic Biomarkers for Pharmaceutical Development - page 130

cellular components [95] . Thus, pre-clinical stages in the drug discovery process require
a multitude of biochemical and genetic assays in order to characterize the effects of drug
candidates on cellular systems and model organisms. Given this complexity, it is natural
to apply proteomics in the drug discovery process to understand the effects of drug can-
didates on their protein targets and shed light on the cellular mechanisms resulting in the
observed phenotype. Over the last 15 years, proteomics technology has made significant
progress in several areas and has become an important tool at various stages in drug dis-
covery [96] .
The terms metabolomics and metabonomics are often used interchangeably [34] .
Metabolomics technology has been part of drug discovery and development for over a dec-
ade, and has gained early and wide acceptance as a novel tool for the rapid elucidation of
mechanisms and biomarkers in pre-clinical discovery [97,98] . It allows comprehensive and
simultaneous profiling of hundreds of discrete biologically important molecules, including
amino acids, sugars, lipids, and exogenous substances from biological fluids and tissues
[99,100] . Metabolomics is one of the 'omics' approaches that mostly represents the interplay
of internal biological regulation and external environmental influences on disease, thereby
being of particular importance to disease mitigation and management [101] .
Since many metabolites are species-independent and evaluated in non-invasively
obtained biofluids, metabolomics-derived biomarkers can potentially have a large impact
on clinical and translational science [102] . Early on, translational biomarkers for drug
safety demonstrated the promise of metabolomics approaches [103-105] . It was reported
that pre-dose metabolomic measures in rat urine could be used to predict the postdate
outcome to acetaminophen treatment [106] . Further research demonstrated a similar
phenomenon in humans where samples taken shortly after dosing with acetaminophen
predicted later hepatic sensitivity [107] . Under a recent Food and Drug Administration
(FDA) Guidance for Industry, biomarkers discovered using metabolomics may be submit-
ted for consideration as new drug development tools and entered into a formal biomarker
qualification process [108] .
6.4 TOXIC OGENOMICS IN DRUG DISCOVERY AND DEVE LOPMENT
Drug development has become much more difficult and challenging than ever, as both
scientific advances and regulatory concerns have led this process to become more rigid,
more expensive, and more risky [109] . Drug toxicity and adverse drug reactions (ADRs)
have been major problems in the development and clinical applications of drugs. Currently,
there is no simple way to predict whether a patient will respond well, badly or have no
response to a drug. There is no 'one size fits all' system for the pharmaceutical companies in
developing drugs [110-112] . To address this issue, toxicogenomic studies have been applied
early in the drug discovery pipeline for the last two decades, often using a classification
approach to group novel and reference compounds so as to predict potentially the toxic-
ity of drug candidates [113,114] ; the industry is now target and hypothesis rich. The central
challenge for today and for the future will be to identify chemicals of sufficient specificity by
exploiting modern molecular biological insights.