Mass Spectrometry as a Workhorse for Preclinical Drug Discovery: Special Emphasis on Drug Metabolism and Pharmacokinetics

Mass spectrometry as an instrument is popular, given its sensitivity, selectivity, speed and robustness. In this chapter, we have briefly deliberated on various mass spec platforms, their hardware components and specific applications in preclinical drug discovery with a special emphasis on drug metabolism and pharmacokinetic assays. Basic principle of operation of mass spectrometer and various ionization techniques/mass analyzers was explicitly discussed. Compatibility of mass spectrometers with ultrafast LC and various throughput techniques, enabled evaluation of thousands of compounds with quick turnaround times. Faster generation of results corresponding to in vitro ADME and in vivo pharmacokinetic assays, aid medicinal chemists to refine their combinatorial synthetic chemistry efforts and expedite the lead optimization and identification phases of drug discovery. Mass spectrometer is a powerful tool for both qualitative and quantitative applications. While quantitative applications include measurement of absolute/relative concentrations, qualitative features assist in identification of molecular structures of metabolites and putative biotransformation pathways. Qualitative inputs are more precise and accurate, with the advent of high-resolution mass spectrometry technology. Although, mass spectrometry has many built-in advantages, it also suffers from matrix effects, as the samples analyzed are mostly of biological origin and are complex in nature. In this chapter, we have defined the nature of matrix effects and various approaches by which these matrix effects can be mitigated