The Current Status of Metabolomics in Drug Discovery and Development

Abstract

Preclinical Research Metabolomics technology has been part of pharmaceutical discovery and development for over a decade and a half. Like many new technologies embraced by the industry, metabolomics gained early and wide acceptance as a novel tool for the rapid elucidation of mechanisms and biomarkers in preclinical discovery only to fall victim to overhype and overpromise. While many dedicated metabolomic groups have disappeared from industry, the academic world has embraced the technology and important new advances have been made such that the technology is beginning to reemerge in the industrial setting. Advances in instrumentation and data analyses have led the way in this resurgence followed by important new clinical applications. The technology has come a long way in the last decade, and we can anticipate an even more exciting ride in the next.

Metabolomics in the pharmaceutical industry

“…As a simple example, most protocols for animal studies include an overnight fast prior to necropsy. While this might seem innocuous and consistent with clinical situations where humans are also frequently required to fast before providing blood or urine samples, an overnight fast has a much larger impact on the rodent metabolome than that of the human [4]. Similarly, the metabolomic signatures relative to control in liver extracts from humans with nonalcoholic steatohepatitis (NASH) are not in complete concordance with those from a common rat NASH model [27].…”

“…Metabolomic studies measure this breadth of molecules and allow correlation of endogenous biochemical composition with different states of an organism to provide (1) a deeper biochemical understanding of phenotypes, (2) a facile platform for mechanistic hypothesis generation and testing, and (3) potential biomarkers for monitoring safety or efficacy. In the context of most pharmaceutical applications, it is desirable to reliably measure as many endogenous metabolites as possible to maximize the coverage of expected biochemical pathways while gaining insight into any unexpected perturbations [4]. More than just an analytical exercise, a successful metabolomic study requires close coordination amongst a diverse set of experts who are engaged at different times, but have familiarity with all aspects of the study.…”

“…Furthermore, since a portion of the measured metabolome overlaps between the methods, the use of both offers a comforting degree of redundancy. The scope of this commentary necessitates only a passing mention of these sophisticated modalities, while several recent reviews [4,[6][7][8][9][10][11][12][13][14] and other contributions in this issue provide more detail. As already mentioned, urine and plasma or serum are the most common matrixes for metabolomic evaluation, since these can be obtained in a serial manner without sacrificing the animal under study and are readily translated into the clinic.…”

“…Conversely, the broad lipoprotein signals in serum or plasma and additional anti-coagulant signals in some plasma samples can complicate small molecule assessments by NMR, even in protein-precipitated samples [15]. To account for the typical variability in dilution expected for urine samples, numerous normalization approaches have been developed for both LC-MS [16] and NMR [4].…”

“…1). This academic surge is significantly advancing the field, creating new interest in metabolomics as a useful tool for the elucidation of biochemical mechanisms and setting the stage for broader applications in the industry [4]. Herein, we will discuss the predominant analytical modalities, applications of highest relevance to pharmaceutical research and development, and remaining challenges for metabolomics to deliver on its full potential.…”