Abstract
Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics is a powerful tool for identifying and quantifying proteins in biological samples, outperforming conventional antibody-based methods in many aspects. LC-MS/MS-based proteomics studies have revealed the protein abundances of many drug-metabolizing enzymes and transporters (DMETs) in tissues relevant to drug metabolism and disposition. Previous studies have consistently demonstrated marked interindividual variability in DMET protein expression, suggesting that varied DMET function is an important contributing factor for interindividual variability in pharmacokinetics (PK) and pharmacodynamics (PD) of medications. Moreover, differential DMET expression profiles were observed across different species and in vitro models. Therefore, caution must be exercised when extrapolating animal and in vitro DMET proteomics findings to humans. In recent years, DMET proteomics has been increasingly utilized for the development of physiologically based pharmacokinetic models, and DMET proteins have also been proposed as biomarkers for prediction of the PK and PD of the corresponding substrate drugs. In sum, despite the existence of many challenges in the analytical technology and data analysis methods of LC-MS/MS-based proteomics, DMET proteomics holds great potential to advance our understanding of PK behavior at the individual level and to optimize treatment regimens via the DMET protein biomarker-guided precision pharmacotherapy.
Highlights
Interindividual variability in drug disposition, i.e., absorption, distribution, metabolism, and excretion (ADME), is often associated with insufficient therapeutic effects and unexpected adverse drug events [1,2,3]
A The number of “+” indicates the performance of a specific technique with “+ + + +” denoted to the best performance and “+” for the lowest performance. b The prevalence of each technique used in drug-metabolizing enzymes and transporters (DMET) proteomics research was estimated from the literature collected by the writing of this paper (May, 2020)
Since the correlations between mRNA expression and protein expression are poor for many DMETs [9,10,11], the influence of alternative splicing variants on DMET function may need to be evaluated at the protein level using appropriate proteomics assays
Summary
Interindividual variability in drug disposition, i.e., absorption, distribution, metabolism, and excretion (ADME), is often associated with insufficient therapeutic effects and unexpected adverse drug events [1,2,3]. Some conventional antibody-based assays, such as enzyme-linked immunosorbent assays (ELISAs) and Western blots, have been widely used for protein expression analysis. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as an important technique for protein identification and quantification This technique has several advantages over conventional antibody-based assays. We discuss the potential clinical applications of DMET proteomics, including the use of DMET protein expression data in the development of physiologically based pharmacokinetic (PBPK) models and the discovery of DMET protein biomarkers for precision pharmacotherapy. The use of “top-down” proteomics in ADME research is uncommon, and most DMET protein analyses were conducted using “bottom-up” methods. “Bottom-up” approaches can be further categorized into targeted and nontargeted (global) proteomics
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