Recent Advances in the Use of Stable Isotopes in Drug Metabolism Research

Baillie, Thomas A.; Rettenmeier, Albert W.

doi:10.1002/j.1552-4604.1986.tb03562.x

Cited by 26 publications

(20 citation statements)

References 51 publications

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“…The use of 13 C labeled drugs is well established as a reliable method for establishing drug pharmacokinetics. [14][15][16] Moreover, in this particular instance, the incorporation of an additional four mass units in analytical standards of the labeled drug and its metabolite ensures sufficient mass differentiation when compared with unlabeled material, thus establishing its usefulness for HPLC/MS analysis in bioavailability studies.…”

Section: Introductionmentioning

confidence: 97%

A convenient synthesis of ¹³C₄‐Leflunomide and its primary metabolite ¹³C₄‐A77 1726

Faragher

Motto

Kaminski³

et al. 2003

Labelled Comp Radiopharmac

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SummaryA convenient synthesis of leflunomide and its primary pharmacologically active metabolite A77 1726, each labeled with four 13 C atoms has been achieved. Starting from 13 C 4 -ethyl acetoacetate, each step of the synthesis proceeds in 60-82% yield. Analysis of the mass spectra of the labeled and unlabeled materials demonstrates that the compounds prepared herein will be suitable as analytical standards for bioavailability studies.

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Section: Introductionmentioning

confidence: 97%

A convenient synthesis of ¹³C₄‐Leflunomide and its primary metabolite ¹³C₄‐A77 1726

Faragher

Motto

Kaminski³

et al. 2003

Labelled Comp Radiopharmac

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“…D 4 -brimonidine, where four deuteriums occupied the 4 0 and 5 0 -carbon positions of the imidazoline ring, was incorporated in the studies. It has been reported that slight differences in physio-chemical properties and differences in metabolite kinetics may exist between deuterated and non-labelled compounds (Bailie and Rettenmeier 1986), however, these effects were not quantitatively evaluated in this study. Examination of the mass spectra of metabolites in liver microsomes/aldehyde oxidase incubations of an equimolar mixture of brimonidine and D 4 -brimonidine revealed the loss of two hydrogens at the 4 0 , 5 0 -positions of imidazoline ring for dehydro-hydroxybrimonidine and no hydrogen loss at the 4 0 , 5 0 -positions of the imidazoline ring for oxo-hydroxybrimonidine and hydroxyquinoxaline.…”

Section: Stable Label D 4 -Brimonidine and Metabolite Characterizationmentioning

confidence: 82%

Characterization of benzimidazole and other oxidative and conjugative metabolites of brimonidinein vitroand in ratsin vivousing on-line H/D exchange LC-MS/MS and stable-isotope tracer techniques

Rowe

Heidelbaugh

et al. 2007

Xenobiotica

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The characterization of brimonidine metabolites presents some challenges since brimonidine and its metabolites generate few structurally informative fragment ions in the LC-MS/MS spectra. The objective of the current study is to use on-line hydrogen/deuterium (H/D) exchange LC-MS/MS and stable-isotope tracer techniques to further characterize unknown brimonidine metabolites in vitro and in vivo. Brimonidine and D4-brimonidine were co-incubated in rat and human microsomes and rabbit aldehyde oxidase in vitro. In addition, the urine was collected from rats co-administered orally with brimonidine and D4-brimonidine. The hepatic microsomal and urinary metabolites were then characterized by H/D LC-MS/MS system. In addition to previously characterized 2-oxobrimonidine, 3-oxobrimonidine and 2,3-dioxobrimonidine, the results show that oxidation occurs at quinoxaline ring producing oxo-hydroxybrimonidine and hydroxyquinoxaline metabolites. The hydroxyquinoxaline metabolite was only observed in microsomal incubations with hydroxylation at the 7- or 8- position. The dehydro-hydroxybrimonidine metabolites were characterized as 2-oxo or 3-oxo -4', 5'-dehydrobrimonidine. A novel metabolite ((4-bromo-lH-benzoimidazol-5-yl)-imidazolidin-2-ylidene-amine) of benzimidazole derivative of brimonidine in rats in vivo was identified and confirmed with reference standard. In conclusion, on-line H/D exchange LC-MS/MS and stable-isotope tracer techniques are useful for the characterization of brimonidine metabolites.

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“…The relatively small number of 13 C, 15 N, or 17,18 O-labelled precursors exacerbates this problem, making the synthesis of the labelled drug often more difficult than that of the parent compound. The increased sensitivity and widespread availability of modern NMR and high-resolution mass spectrometers will increase the application of stable isotopes to study drug metabolism.…”

Section: Resultsmentioning

confidence: 99%

“…For the purposes of this perspective stable isotope labelling (SIL) is limited to specific enrichment with the low abundance stable isotopes 2 H, 13 C, 15 N, or 17,18 O. For the convenience of the reader, some properties of these isotopes are listed in Table 1.…”

Section: Introductionmentioning

confidence: 99%

The use of stable isotope labelling for the analytical chemistry of drugs

Ünkefer

Martinez

2011

Drug Testing and Analysis

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This perspective reviews the potential for stable isotope labelling to examine the metabolic transformations of drugs. The increased sensitivity and widespread availability of modern nuclear magnetic resonance (NMR) and high-resolution mass spectrometers will increase the application of stable isotopes to study drug metabolism. Creating mass doublets by mixing a natural isotopic abundance compound with a labelled isotopomer and applying stable isotope filtering to high resolution mass spectrometry allows one to rapidly identify drug metabolites in very complex samples, such as blood or urine. Applying this approach to drug metabolism will require a significant synthesis effort. The relatively small number of (13) C, (15) N, or (17,18) O-labelled precursors exacerbates this problem, making the synthesis of the labelled drug often more difficult than that of the parent compound. We have developed new strategies for stable isotope labelling of complex molecules based on the rich chemistry of [(13) C]methyl phenyl sulfide, where the phenylthio group acts as a stable, non-volatile carrier for the valuable (13) C-label. For example we have used [(13) C]methyl phenyl sulfide to prepare the three possible (13) C-isotopomers ([1-(13) C]-, [2-(13) C]-, [1,2-(13) C(2) ]) of the two carbon precursors, ethyl 2-(phenylthio) acetate and ethyl N,N-dimethyl oxamate. In each case, these two-carbon labelling precursors are asymmetric and the differential reactivity of the carbons allows for either/or (13) C-labelling in the products. We demonstrate the utility of these two carbon precursors in the synthesis of aromatic ring-labelled N-(4-hydroxyphenyl)acetamide (acetaminophen or paracetamol).

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Recent Advances in the Use of Stable Isotopes in Drug Metabolism Research

Cited by 26 publications

References 51 publications

A convenient synthesis of ¹³C₄‐Leflunomide and its primary metabolite ¹³C₄‐A77 1726

A convenient synthesis of ¹³C₄‐Leflunomide and its primary metabolite ¹³C₄‐A77 1726

Characterization of benzimidazole and other oxidative and conjugative metabolites of brimonidinein vitroand in ratsin vivousing on-line H/D exchange LC-MS/MS and stable-isotope tracer techniques

The use of stable isotope labelling for the analytical chemistry of drugs

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Recent Advances in the Use of Stable Isotopes in Drug Metabolism Research

Cited by 26 publications

References 51 publications

A convenient synthesis of 13C4‐Leflunomide and its primary metabolite 13C4‐A77 1726

A convenient synthesis of 13C4‐Leflunomide and its primary metabolite 13C4‐A77 1726

Characterization of benzimidazole and other oxidative and conjugative metabolites of brimonidinein vitroand in ratsin vivousing on-line H/D exchange LC-MS/MS and stable-isotope tracer techniques

The use of stable isotope labelling for the analytical chemistry of drugs

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A convenient synthesis of ¹³C₄‐Leflunomide and its primary metabolite ¹³C₄‐A77 1726

A convenient synthesis of ¹³C₄‐Leflunomide and its primary metabolite ¹³C₄‐A77 1726