The drug discovery process has been dramatically accelerated with the introduction of combinatorial chemistry for selection of new lead drug candidates. A central theme underlying this new technology is the capability to synthesize a myriad of new chemical entities with randomized structural variations. While the promise and opportunities are significant, combinatorial approaches pose several challenging tasks that must be met in order to realize the full potential of this technology. One of the challenges has been to develop fast, sensitive, and reliable high-throughput analytical methods to support investigations conducted in animals and humans. These include early pharmacokinetics screening, metabolic profiling, toxicokinetics, formulation, and eventually clinical studies. Such methods in analytical chemistry have the potential to initiate a paradigm transition in drug discovery landscape from rather laborious and time-consuming steps to that of an accelerated campaign for lead optimization. Among the many intriguing avenues, mass spectrometry is arguably an indispensable analytical tool and a pragmatic approach for the identification and quantification of pharmaceutical products in biological fluids (e.g., plasma, serum, whole blood. and urine). Herein, we present a description of several laboratory procedures that have been successfully deployed to a diverse collection of issues during drug discovery and development. Techniques such as high-throughput off-line sample processing, on-line sample extraction, fast chromatographic separations, and parallel (multiplexed) liquid chromatography in conjunction with mass spectrometry are discussed.
