Quantitative targeted absolute proteomics-based ADME research as a new path to drug discovery and development: Methodology, advantages, strategy, and prospects

Abstract

An understanding of the functional roles of proteins, for example, in drug absorption, distribution, metabolism, elimination, toxicity, and efficacy (ADMET/efficacy), is important for drug discovery and development. Equally, detailed information about protein expression is required. Recently, a new protein quantification method, called quantitative targeted absolute proteomics (QTAP), has been developed on the basis of separation and identification of protein digests by liquid chromatography-linked tandem mass spectrometry with multiple reaction monitoring. Target peptides for quantification are selected only from sequence information, so time-consuming procedures such as antibody preparation and protein purification are unnecessary. In this review, we introduce the technical features of QTAP and summarize its advantages with reference to recently reported results. These include the evaluation of species differences of blood-brain barrier protein levels among human, monkey, and mouse. The high selectivity of QTAP and its ability to quantify multiple proteins simultaneously make it possible to determine the absolute expression levels of many proteins in tissues and cells in both physiological and disease states. Knowledge of absolute expression amounts, together with data on intrinsic protein activity, allows us to reconstruct in vivo protein function, and this should be an efficient strategy to predict ADMET/efficacy of drug candidates in humans in various disease states. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association.