Metabonomics in Toxicity Assessment PDF

Preface

The role of the toxicologist in the pharmaceutical industry has changed significantly over the past 10 years. Historically, the toxicologist's responsibilities were often thought by their colleagues in pharmaceutical companies as being akin to that of the grim reaper whose appearance at project team meetings, presaged bad tidings for the future of the drug under consideration. This news was seldom received before a significant investment in time and resources had already been placed in the development of the drug and cancellation of the project due to drug toxicity, meant a significant setback. However, the paradigm for development of new chemical entities has changed significantly in recent years. Toxicologists are now required to help in prelead prioritization to help manage the wealth of hits coming out of combinatorial synthesis and high throughput screening, with the goal of improving preclinical throughput by decreasing the number of failures due to untoward toxicity in safety studies. In silico and in vitro approaches certainly have a place in early toxicity assessment, but there frequently comes a point at which further distinction by these approaches is not possible or is self-defeating in terms of teasing out the real significance of any data. In vivo evaluation still remains the gold standard for safety assessment and will remain so for the foreseeable future, given the regulatory requirements for new drugs. Therefore techniques that enable rapid and=or more complete assessment of in vivo studies are of great interest to pharmaceutical toxicologists.

A number of data–rich technologies have become available for toxicity studies. Among these, metabonomics represents a promising approach that enables relatively rapid throughput in vivo toxicity assessment, frequently providing basic biochemical information not typically available in standard clinical pathology assessment. Therefore, a byproduct (or arguably the primary product) of the technique is identification of individual biomarkers or combinations of biomarkers that can be associated with the toxicity, and which could act as surrogate endpoints. These biomarkers can be used for further prelead prioritization or may prove useful later in development for clinical assessment of toxicity. Clearly, metabonomic technology represents a promising means to achieve the goal of faster drug development with decreased preclinical and clinical failure rates due to toxicity.

Metabonomics serves as one leg of the triad of ‘‘omic'' technologies that includes transcriptomics (also known as toxicogenomics in toxicology circles) and proteomics. Although these other omic technologies are not the subject of this volume, it has become apparent to practitioners in the field, that a ‘‘systems'' approach to toxicity evaluation that incorporates two or preferably all three omic approaches enables a synergy of data generation and more importantly data interpretation that is not possible with any one ‘‘omic'' technology. While much has been written about transcriptomics and to a lesser extent proteomics, very little is available to the toxicologist considering use of metabonomic technology. This volume is meant to help fill that void.

Metabonomics can enable rapid generation of a mountain of data. However, generating mountains is not the role of the pharmaceutical toxicologist, whose goal is to refine the mountain down to the valuable jewels of mechanistic-based safety screens and biomarkers. This is easier said than done, and this volume provides some essential wisdom for sifting through the tailings to find the jewels. Like other ‘‘omic'' technologies, experimental designs, protocol conduct, and proper control are absolutely imperative to metabonomics. Some of the essential tools for the toxicologist evaluating metabonomic technology are covered in some detail in the volume including analytical, biological, and chemometric considerations. Additionally, varied applications are presented which provide a flavor for what metabonomics can do.

The aim of this book is to present a summary of the use of metabonomics in the safety assessment of new chemical entities. Although a presentation of the instrumentation and methods that are required to perform biofluid NMR will be made for purposes of completeness, the main focus of the text will deal with the use of the technique by toxicologists to aid in safety assessment of novel prelead candidates with further application to biomarker identification. Given the limited exposure metabonomics has within the toxicology community, little background knowledge is assumed and each contributor has attempted to identify methods and materials used to generate data and to explain any assumptions made in their evaluations. This balanced critique of the present state of the art hopefully encompasses both the strengths and weaknesses of the technology. We believe that this book will serve as a basic reference tool, since each chapter provides a comprehensive bibliography. The worldwide pharmaceutical toxicologist and other preclinical and clinical scientists involved in safety assessment are the intended audience for this volume, although anyone involved in generating and=or interpreting safety data on chemical entities or anyone who has an interest in metabonomics and systems biology as an academic pursuit will find the reference thought provoking and useful.