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.
Keywords: ADMET, biomarker, differential quantitation, drug metabolites, mass spectrometry, metabolomics, stable isotope labeling
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