2018 Volume 3 Issue 2 Pages 47-54
Pharmacokinetics play an important role in drug discovery and development from an early phase and contribute to clinical treatment success by reducing and predicting severe drug-drug interactions and side effects. Drug-metabolizing enzymes and drug-transporters are key regulators of the absorption, distribution, metabolism, and excretion of xenobiotics. Recent studies have demonstrated that the expression levels of proteins related to drug-metabolizing enzymes and drug-transporters in the liver, kidney, and small intestine are highly correlated with those organ’s functional activities. Thus, the quantification of protein expression of drug-metabolizing enzymes and drug-transporters in tissues is essential to clarify and predict pharmacokinetics of xenobiotics, including drugs. Multiple reaction monitoring (MRM)-based targeted proteomics is available to determine protein expression levels using stable isotope-labeled internal standard peptides. However, MRM analysis records fragments of only targeted precursor ions. Sequential window acquisition of all theoretical mass spectra (SWATH) acquisition, coupled with Quadrupole time-of-flight mass spectrometers, is a data independent approach, which is able to produce a complete and permanent record of all fragment ions of the detectable peptide precursors present in a biological sample. Thus, the quantification of any protein of interest is possible from SWATH MS datasets. To overcome the limitations of MRM-based quantitative proteomics, we applied SWATH-based comprehensive quantitative proteomics to study pharmacokinetics. In this review, we describe the advantages of SWATH-based comprehensive quantitative proteomics for the elucidation of pharmacokinetics.
