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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Metabonomics: using biofluid metabolite profiling to assess pre-clinical hepatotoxicity

Craig E. Thomas, PhD
Division of Toxicology and Drug Disposition,
Lilly Research Laboratories
Metabonomics: using biofluid metabolite profiling to assess pre-clinical hepatotoxicity [PDF]

An organism’s response to stimuli such as drug treatment or environmental changes can be monitored by following alterations in endogenous metabolites, as they represent dynamic changes occurring as a return to homeostasis is sought. Metabonomics generally refers to using high field NMR to measure biofluid or tissue metabolites. The method has been widely used to detect and characterize target organ toxicity, to delineate mechanisms of toxicity, and discover novel biomarkers. For use in early drug safety assessment, the development of predictive chemometric models built from data derived from a number of studies with prototypical toxicants can be used to screen drug candidates for target organ toxicity in a rapid, cost effective manner. We have compared the urinary metabolic profiles of novel compounds obtained in short term rodent studies against a predictive model for hepatotoxicity developed by COMET (Consortium on Metabonomic Toxicology). Overall, the model correctly classified the compounds as hepatotoxicants, and the severity of effect was appropriately rank ordered as compared to the traditional endpoints of clinical and morphologic pathology. These data provide evidence that metabonomics can be used to assess the potential for hepatotoxicity in the early selection of drug candidates.

Biographical Sketch

Dr. Thomas is currently a Research Advisor in the Department of Investigative Toxicology at Lilly Research Laboratories, a division of Eli Lilly & Co., in Indianapolis, IN. He received his B.S. and M.S. degrees in Veterinary Science at Penn State and his Ph.D. in 1986 in Biochemistry and Environmental Toxicology from Michigan State University. Craig was then granted an NIEHS Research Service Award to conduct postdoctoral work at Oregon State where he investigated mechanisms of calcium-dependent hepatocellular injury. From 1980-1996 his academic and pharma industry research efforts focused on the role of free radicals in toxicity and disease, and in the development of pharmaceutical antioxidants. In January 2000, Craig joined the Lilly Development Centre in Brussels, Belgium as Head of Investigative Toxicology and Toxicology Projects. It was here that he began his studies on the use of high field NMR as a tool to study metabolic perturbations induced by xenobiotics. Following his return to the United States in the summer of 2002 he continues to work on the development of metabonomics as an enabling technology to revolutionize clinical and pre-clinical drug development. Dr. Thomas is a member of the Society of Toxicology, and has authored 43 peer reviewed journal articles, 25 invited review articles, holds 4 US patents and is the Co-Editor of the book ‘Oxygen Radicals and the Disease Process.”