Chapter 12 Identification and characterization of drug metabolites using stable isotope techniques

Bjorge, S. M.

doi:10.1016/s0165-7208(97)80159-6

Cited by 7 publications

(1 citation statement)

References 24 publications

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“…An elegant alternative is the use of stable isotope labeled drug analogues. Mixtures of labeled and unlabeled drug yield a characteristic isotopic pattern during MS analysis, which can be used to help identify metabolites 9–12. This approach, which is particularly advantageous in the case that unexpected or atypical biotransformations occur, was chosen for the elucidation of the metabolic pattern of BAL19403 in conjunction with structural elucidation of the observed metabolites.…”

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confidence: 99%

Elucidation of the in vitro metabolic profile of stable isotope labeled BAL19403 by accurate mass capillary liquid chromatography/quadrupole time‐of‐flight mass spectrometry and isotope exchange

Wind

Gebhardt

Grunwald

et al. 2007

Rapid Comm Mass Spectrometry

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The in vitro metabolic pattern of BAL19403, a novel macrolide antibiotic, was investigated by capillary liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QTOF-MS) in incubations with human microsomes. For the elucidation of the metabolic pathway, BAL19403 labeled with four deuterium atoms (D4) was used, and detection of metabolites performed using mixtures of the unlabeled (H4) BAL19403 and its D4 analogue (1:1) as substrate. All metabolites appeared with similar chromatographic behavior. MS/MS spectra of BAL19403 and its metabolites are dominated by non-informative fragment ions. Therefore, the structure of the metabolites was elucidated mainly by accurate mass measurements with subsequent proposals of elemental compositions. Main biotransformations were N-demethylation, lactone ring hydrolysis, and oxidation. Additionally, N-dealkylation of the aromatic moiety was identified. This dealkylation results not only in formation of an aldehyde, according to the classical pathway, but also in formation of the corresponding alcohol and carboxylic acid. Final elucidation of their structures was possible, since this dealkylation takes place vicinal to the deuterium-labeled part of BAL19403 and interferes with D/H exchange. The degree of D/H exchange, determined by analysis of the metabolite isotopic pattern, was used to elucidate the adjacent functional group.

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confidence: 99%

Elucidation of the in vitro metabolic profile of stable isotope labeled BAL19403 by accurate mass capillary liquid chromatography/quadrupole time‐of‐flight mass spectrometry and isotope exchange

Wind

Gebhardt

Grunwald

et al. 2007

Rapid Comm Mass Spectrometry

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Common Liquid Chromatography–Mass Spectrometry (LC–MS) Methodology for Metabolite Identification

Klunk

Prakash

2011

Mass Spectrometry in Drug Metabolism and Disposition

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Stable Isotope Techniques in Early Drug Development: An Economic Evaluation

Browne

1998

The Journal of Clinical Pharma

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Stable isotope labeled (SIL) drug methods are compared with standard methods for performing early (phases I and IIa) drug development studies (mass balance, bioavailability, single-dose volunteer and patient, multiple-dose volunteer and patient). SIL methods offer considerable reduction in the cost (> 50%) and number of subjects (67%) required for bioavailability and multiple-dose patient studies. Moreover, a complete early drug development program is described for optimally combining SIL and standard studies, which can reduce cost by 23% and number of subjects by 36% compared with a program using standard methods. These reductions should result in development time savings of at least one year.

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Chapter 12 Identification and characterization of drug metabolites using stable isotope techniques

Cited by 7 publications

References 24 publications

Elucidation of the in vitro metabolic profile of stable isotope labeled BAL19403 by accurate mass capillary liquid chromatography/quadrupole time‐of‐flight mass spectrometry and isotope exchange

Elucidation of the in vitro metabolic profile of stable isotope labeled BAL19403 by accurate mass capillary liquid chromatography/quadrupole time‐of‐flight mass spectrometry and isotope exchange

Common Liquid Chromatography–Mass Spectrometry (LC–MS) Methodology for Metabolite Identification

Stable Isotope Techniques in Early Drug Development: An Economic Evaluation

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