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Following the recent withdrawal of several prominent drugs from US and European markets because of detrimental drug-drug interactions, metabolic drug interactions have received considerable attention in the pharmaceutical industry. In turn, the question of drug safety has received significant legal, regulatory and commercial emphasis, bringing this issue to the forefront of both industry and government drug agendas. The value of predicting the drug interactions of compounds as early as possible in the drug discovery process for all therapeutic areas cannot be underestimated. From 1964 to 1999, approximately 8% of the drugs approved by the FDA were later withdrawn from the US market. Pharmaceutical companies are facing increasing pressure to prove the long-term safety of their products, and this is complicated by the fact that animal models are not perfectly predictive of human responses, and may provide contradictory information. The failure to address safety concerns successfully during the drug optimization process may result in companies withdrawing any approved drugs from the market; drug safety issues not only present human health consequences, but also have a negative economic and public relations impact on the pharmaceutical industry. This paper discusses the significance of drug interactions, and addresses strategies to evaluate the potential of a drug candidate for drug interactions.

Absorption, distribution, metabolism, excretion and toxicology (ADMET) studies are widely used in drug discovery and development to help obtain the optimal balance of properties necessary to convert lead compounds into drugs that are safe and effective for human use. Drug discovery efforts have been aimed at identifying and addressing metabolism issues at the earliest possible stage, by developing and applying innovative liquid chromatography-mass spectrometry (LC-MS)-based techniques and instrumentation, which are both faster and more accurate than prior techniques. Such new approaches are demonstrating considerable potential to improve the overall safety profile of drug candidates throughout the drug discovery and development process. These emerging techniques streamline and accelerate the process by eliminating potentially harmful candidates earlier and improving the safety of new drugs. In the area of drug metabolism, for example, revolutionary changes have been achieved by the combination of LC-MS with innovative instrumentation such as triple quadrupoles, ion traps and time-of-flight mass spectrometry. In turn, most ADMET studies have come to rely on LC-MS for the analysis of an ever-increasing workload of potential candidates. This article provides a discussion on the importance of LC-MS in supporting drug metabolism studies, and highlights the relative merits of current applications for LC-MS in drug metabolism testing and analysis. These applications include in vitro and in vivo testing, pharmacokinetic profiling, chiral separations, stable isotope labeling, metabolic activation testing, metabolite characterization and radiolabeled-drug testing.

Idiosyncratic drug reactions (IDRs; a specific type of drug toxicity characterized by delayed onset) are a major complication of drug therapy that need to be addressed during drug discovery and development. Efforts to improve drug safety are hampered by the lack of an accepted approach to predict IDRs, which in turn is due to the low incidence of occurrence of IDRs and the various potential mechanisms involved in these reactions. The concept of the relative rarity and formation of reactive metabolite of IDRs is briefly described. Hypothetical chemical mechanisms for the formation of reactive metabolites are summarized, including a classification of adverse drug reactions and types of reactive metabolites. The relative merits of current and potential strategies for dealing with reactive intermediates in drug discovery and development are examined, and the significance of covalent binding in drug discovery/development in vitro and in vivo systems is considered. Also discussed are the merits of tools (screening methods to trap reactive intermediates, enzyme inhibition and covalent binding) and strategies for predicting which new drugs have the potential to produce reactive intermediates and IDRs; these approaches may be considered to have the potential to improve the overall safety profile of drug candidates at various stages of the drug discovery and development process.