Applications of Targeted Proteomics in ADME for IVIVE

Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 7)

Abstract

Membrane transporters act as physiological “gatekeepers” that regulate the distribution of endogenous and exogenous compounds. It is therefore imperative that drug discovery/development research considers the function and expression of drug transporters, which can dictate drug concentration to pharmacological targets or may be the drug target themselves. Variation in transporter expression across species and in vitro models is recognized as a major complicating factor encountered during in vitro–in vivo extrapolations that can limit a model’s predictive power. This is particularly problematic in scenarios such as biliary secretion that are dependent upon in vitro and preclinical data due to lack of clinical bile samples. Consequently, quantification of drug transport proteins becomes a fundamental element in establishing important correlations for pharmacokinetic predictions that are of significant interest during drug discovery. In this chapter we provide an overview of methodologies relevant to protein quantification and their important limitations, followed by a review of recent studies in which mass spectrometry-based targeted quantifications of drug transporters are applied in predictions of transporter-mediated drug clearance.

Keywords

Permeability Surfactant Urea Arsene Immobilization 

Abbreviations

ABC

ATP-binding cassette

ADME

Absorption, distribution, metabolism, elimination

AQUA

Absolute quantification

BCRP

Breast cancer resistance protein (human)

Bcrp

Breast cancer resistance protein (other species than human)

BLAST

Basic local alignment search tool

BSEP

Bile salt export pump (human)

Bsep

Bile salt export pump (other species than human)

CHAPS

3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate

CYP

Cytochrome P450

ELISA

Enzyme-linked immunosorbent assays

ESI-Q-TOF

Electrospray ionization quadrupole time of flight

IS

Internal standard

IVIVE

In vitro–in vivo extrapolation

LC

Liquid chromatography

LC-MS/MS

Liquid chromatography tandem mass spectrometry

MDCK

Madin–Darby canine kidney

MDR1

Multidrug resistance protein (P-gp)

MRM

Multiple reaction monitoring

MRP2

Multidrug resistance-associated protein 2 (human)

Mrp2

Multidrug resistance-associated protein 2 (other species than human)

MS

Mass spectrometry

MSD

Membrane-spanning domain

NBD

Nucleotide-binding domain

OATP

Organic anion-transporting polypeptide

P-gp

Multidrug resistance protein (MDR1)

PK

Pharmacokinetics

PSAQ

Protein standard absolute quantification

PTM

Posttranslational modifications

RAF

Relative activity factor

RT-PCR

Reverse transcription polymerase chain reaction

SCH

Sandwich-cultured hepatocyte

SDS

Sodium dodecyl sulfate

SIL

Stable isotope-labeled

SILAC

Stable isotope labeling by amino acids in cell culture

SLC

Solute carrier

SNP

Single nucleotide polymorphisms

TOF

Time of flight

WT

Wild type

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Pfizer Global Research and DevelopmentGrotonUSA

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