Experiments for a systematic comparison between stable-isotope-(deuterium) labeling and radio-(14C) labeling for the elucidation of the in vitro metabolic pattern of pharmaceutical drugs

Grunwald, Helge; Hargreaves, Patrick; Gebhardt, Klaus; Klauer, Dominique; Serafyn, Arnaud; Schmitt‐Hoffmann, Anne; Schleimer, Michael; Schlotterbeck, Goetz; Wind, Mathias

doi:10.1016/j.jpba.2013.07.004

Cited by 6 publications

(3 citation statements)

References 14 publications

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“…Several in vitro and in vivo studies performed using deuterated analogs of these compounds have had profound mechanistic implications. 2 As a result, various syntheses of ring-deuterated variants of acetaminophen 3 and diclofenac 4 have been reported. However, these methods generally require several synthetic steps from expensive deuterated starting materials.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen–deuterium exchange of aromatic amines and amides using deuterated trifluoroacetic acid

Giles

Lee

Jung

et al. 2015

Tetrahedron Letters

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The H-D exchange of aromatic amines and amides, including pharmaceutically relevant compounds such as acetaminophen and diclofenac, was investigated using CF3COOD as both the sole reaction solvent and source of deuterium label. The described method is amenable to efficient deuterium incorporation for a wide variety of substrates possessing both electron-donating and electron-withdrawing substituents. Best results were seen with less basic anilines and highly activated acetanilides, reflecting the likelihood of different mechanistic pathways.

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Section: Introductionmentioning

confidence: 99%

Hydrogen–deuterium exchange of aromatic amines and amides using deuterated trifluoroacetic acid

Giles

Lee

Jung

et al. 2015

Tetrahedron Letters

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“…Drug metabolism, forensic analyses and doping control are also growing areas of stable isotope applications. Stable isotope and radioisotope-based quantifications in drug metabolism show a good agreement of their quantitative results (e.g., Grunwald et al, 2013). The number of drugs identifiable in a single LC-MS run was pushed forward (Gergov, Orejanper€ a, & Vuori, 2003;Mueller et al, 2005).…”

Section: Quantification Of Small Molecules In Body Fluidsmentioning

confidence: 87%

A timeline of stable isotopes and mass spectrometry in the life sciences

Lehmann

2016

Mass Spec Rev

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This review retraces the role of stable isotopes and mass spectrometry in the life sciences. The timeline is divided into four segments covering the years 1920-1950, 1950-1980, 1980-2000, and 2000 until today. For each period methodic progress and typical applications are discussed. Application of stable isotopes is driven by improvements of mass spectrometry, chromatography, and related fields in sensitivity, mass accuracy, structural specificity, complex sample handling ability, data output, and data evaluation. We currently experience the vision of omics-type analyses, that is, the comprehensive identification and quantification of a complete compound class within one or a few analytical runs. This development is driven by stable isotopes without competition by radioisotopes. In metabolic studies as classic field of isotopic tracer experiments, stable isotopes and radioisotopes were competing solutions, with stable isotopes as the long-term junior partner. Since the 1990s the number of metabolic studies with radioisotopes decreases, whereas stable isotope studies retain their slow but stable upward tendency. Unique fields of stable isotopes are metabolic tests in newborns, metabolic experiments in healthy controls, newborn screening for inborn errors, quantification of drugs and drug metabolites in doping control, natural isotope fractionation in geology, ecology, food authentication, or doping control, and more recently the field of quantitative omics-type analyses. There, cells or whole organisms are systematically labeled with stable isotopes to study proteomic differences or specific responses to stimuli or genetic manipulation. The duo of stable isotopes and mass spectrometry will probably continue to grow in the life sciences, since it delivers reference-quality quantitative data with molecular specificity, often combined with informative isotope effects. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:58-85, 2017.

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“…The use of radiolabeled chemicals is essential for understanding drug disposition during drug development. , Most pharmaceutical companies synthesize isotopically labeled compounds for covalent binding studies at the lead optimization stage of drug discovery. After both in vitro or in vivo studies, radioactive drugs covalently bound to proteins can be detected using accelerated mass spectrometry (AMS) or liquid scintillation counting (LSC) .…”

Section: Mass Spectrometric Characterization and Quantification Of Dr...mentioning

confidence: 99%

Mass Spectrometric and Functional Aspects of Drug–Protein Conjugation

Tailor

Waddington

Meng

et al. 2016

Chem. Res. Toxicol.

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The covalent binding of drugs (metabolites) to proteins to form drug-protein adducts can have an adverse effect on the body. These adducts are thought to be responsible for idiosyncratic drug reactions including severe drug hypersensitivity reactions. Major advances in proteomics technology have allowed for the identification and quantification of target proteins for certain drugs. Human serum albumin (HSA) and Hb have been identified as accessible targets and potential biomarkers for drug-protein adducts formation, for numerous drugs (metabolites) including β-lactam antibiotics, reactive drug metabolites such as quinone imines (acetaminophen) and acyl glucuronides (diclofenac), and covalent inhibitors (neratinib). For example, MS/MS analysis of plasma samples from patients taking flucloxacillin revealed that flucloxacillin and its 5-hydroxymethyl metabolite formed covalent adducts with lysine residues on albumin via opening of the β-lactam ring. Other proteins such as P450 and keratin are also potential targets for covalent binding. However, for most drugs, the properties of these target proteins including their location, their quantity, the timing of conjugate generation, and their biological function are not well understood. In this review, currently available proteomic technologies including MS/MS analysis to identify antigens, precise location of modifications, and the immunological consequence of hapten-protein complex are illustrated. Moving forward, identification of the nature of the antigenic determinants that trigger immune responses to drug-protein adducts will increase our ability to predict idiosyncratic toxicity for a given compound.

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Experiments for a systematic comparison between stable-isotope-(deuterium) labeling and radio-(14C) labeling for the elucidation of the in vitro metabolic pattern of pharmaceutical drugs

Cited by 6 publications

References 14 publications

Hydrogen–deuterium exchange of aromatic amines and amides using deuterated trifluoroacetic acid

Hydrogen–deuterium exchange of aromatic amines and amides using deuterated trifluoroacetic acid

A timeline of stable isotopes and mass spectrometry in the life sciences

Mass Spectrometric and Functional Aspects of Drug–Protein Conjugation

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