Editorial [Hot Topic: High Throughput In Vitro ADME/Tox Profiling for Drug Discovery(Guest Editor: Edward H. Kerns)]

Drug discovery research is multidisciplinary and relies on many surrogate indicators of human success. The process of drug discovery seeks to carefully optimize and balance these indicators. ADME/Tox properties have emerged in drug discovery over the last decade as important indicators. Current Drug Metabolism is a forum for research in this field and the Editor, Dr. Chandra Prakash, identified the value of an ensemble of articles on in vitro ADME/Tox profiling for drug discovery. Consequently, an international faculty of experts in the field prepared timely and valuable reviews that provide an outstanding state-of-the-art foundation, set high standards, and provide a vision for the impact that is achievable for drug discovery through the collaborations of ADME/Tox scientists. It is important to consider the specific goals and processes of drug discovery because they differ from other areas of pharmaceutical development. Discovery uses flexible and wide-ranging experimentation to learn about new diseases, characterize new targets, and design novel compounds that balance acceptable structure-activity relationships for hundreds of variables. These variables include target binding, function, selectivity, delivery, and safety. In vitro assays are indicators that guide discovery scientists toward the optimum clinical candidate. In vitro assays have crucial roles in all aspects of drug discovery, including biology, chemistry and ADME/Tox, because they provide many research opportunities. They enable rapid assessment of thousands of compounds for the same selected variable, owing to their ease of automation for parallel experimentation. In vitro assays examine a very specific physicochemical property or biochemical activity that allows specific conclusions, compared to the many possible interacting properties in complex biological systems (e.g., cell, organism). In vitro assays are amenable to problem solving, owing to the ease of control of specific experimental conditions to ask a specific research question. Conversely, specific variables that might determine the rate or outcome in complex systems can be rapidly diagnosed because in vitro studies can individually test each contributing property in parallel. For example, low bioavailability can be diagnosed to solubility, permeability or metabolic stability. Creatively applied, in vitro assays provide profoundly valuable tools for drug discovery scientists. Occasionally, in vitro assays are said by discovery scientists to be unpredictive of in vivo behaviors. For example, microsomal stability half-life might be stated to be unpredictive of pharmacokinetic (PK) half-life. Such characterizations do not take into account that in vivo behaviors, such as half-life, are the result of multiple properties (e.g., Phase I and Phase II metabolism, biliary and renal clearance, plasma stability, volume of distribution). Thus, drug discovery scientists are aided by a broader understanding of the complexity of living systems and the many properties that can affect an in vivo observation. To this end, the authors of the following reviews have endeavored to provide a context for how the data should be applied in drug discovery. There is no doubt that drug discovery research teams, which are usually comprised of chemists and biologists, are greatly benefited by enhanced knowledge of ADME/Tox, as well as the collaboration of specialists in ADME/Tox effects, experiment planning and interpretation. Authors of the following reviews have provided guidance on assay pitfalls and best practices, as well as examples of in vitro-in vivo correlations. Scientists who perform in vitro assays are well advised to carefully implement and validate their assays. Data should also be obtained on the correlation of their assay data to behaviors (e.g., PK, toxicity) of compounds in complex biological systems. This insures that drug discovery project teams are not mislead and have accurate information to indicate pathways to success.