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Isotopic Labeling of Metabolites in Drug Discovery Applications

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Understanding the metabolic and pharmacokinetic fate of a drug in humans is a key factor in its development and registration, as well as in the elaboration of new therapeutic agents. To carry out these studies, stable isotope labeling techniques have been effectively used by drug metabolism scientists and toxicologists in order to gain better understanding of the drugs’ disposition, bioavailability and toxicity in in vivo studies. Among the different analytical techniques used, mass spectrometry (MS) coupled to separation techniques has become the detection method of choice due to its high sensitivity and selectivity. In vitro quantification of metabolite levels in biofluids by MS is often difficult if a proper internal standard is not available due to the inherent problems associated with the technique (e.g. chromatographic coelutions, ion suppression, low reproducibility etc.). Stable isotope coding approaches alleviate these drawbacks and allow comparative drug metabolomics studies similarly to the differential proteomic techniques developed in the last decade. This review describes a selection of methodological improvements in the use of stable isotopes labeling in combination with MS to detect drug metabolites. In the first part of the paper, the application of labeled compounds to study the absorption, distribution, metabolism, excretion and toxicology of drugs (ADMET) in addition to the elucidation of metabolic pathways is presented. In the second part, recent developments of stable isotope coded tags for the in vitro relative metabolite quantification in biofluids are presented.
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Keywords: ADMET; biomarker; differential quantitation; drug metabolites; mass spectrometry; metabolomics; stable isotope labeling

Document Type: Research Article

Publication date: November 1, 2012

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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