TY - JOUR
T1 - Quantitative targeted absolute proteomics-based ADME research as a new path to drug discovery and development
T2 - Methodology, advantages, strategy, and prospects
AU - Ohtsuki, Sumio
AU - Uchida, Yasuo
AU - Kubo, Yoshiyuki
AU - Terasaki, Tetsuya
N1 - Funding Information:
The studies mentioned in this review were supported in part by a Grant for Development of Creative Technology Seeds Supporting Program for Creating University Ventures from Japan Science and Technology Agency (JST), and the Industrial Technology Research Grant Program from New Energy and the Industrial Technology Development Organization of Japan, as well as a Grant-in-Aid for Scientific Research (S) 18109002 from the JSPS, a Grant-in-Aid for Scientific Research on Priority Area 17081002 from The Ministry of Education, Culture, Sports, Science, and Technology Japan, and a grant for Creation of Strategic Innovation Project from JST.
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - Blood-brain barrier
KW - CYP enzyme
KW - Mass spectrometry
KW - Pharmacokinetics
KW - Pharmacoproteomics (PPx)
KW - Proteomics
KW - Quantitative targeted absolute proteomics (QTAP)
KW - Receptor
KW - Transporter
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U2 - 10.1002/jps.22612
DO - 10.1002/jps.22612
M3 - Review article
C2 - 21560129
AN - SCOPUS:79960116572
VL - 100
SP - 3547
EP - 3559
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
SN - 0022-3549
IS - 9
ER -