Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity

An increased diversity of therapeutic targets in the pharmaceutical industry in recent years has led to a greater diversity of toxicological effects. This, and the increased pace of drug discovery, leads to a need for new technologies for the rapid elucidation of toxicological mechanisms. As part of an evaluation of the utility of metabonomics in drug safety assessment, H-1 NMR spectra were acquired on urine and liver tissue samples obtained from rats administered vehicle or a development compound (MrkA) previously shown to induce hepatotoxicity in several animal species. Multivariate statistical analysis of the urinary NMR data clearly discriminated drug-treated from control animals, due to a depletion in tricarboxylic acid cycle intermediates, and the appearance of medium chain dicarboxylic acids. High-resolution magic angle spinning NMR data acquired on liver samples exhibited elevated triglyceride levels that were correlated with changes in the urinary NMR data. Urinary dicarboxylic aciduria is associated with defective metabolism of fatty acids; subsequent in vitro experiments confirmed that MrkA impairs fatty acid metabolism. The successful application of metabonomics to characterize an otherwise ill-defined mechanism of drug-induced toxicity supports the practicality of this approach for resolving toxicity issues for drugs in discovery and development.