Applications of Tandem Liquid Chromatography/Mass Spectrometry in Drug Biotransformation and Quantification Studies

Dulik, Deanne M.; Schaefer, William H.; Bordas-Nagy, Joseph; Simpson, Richard; Murphy, D.M; Rhodes, Gerald R.

doi:10.1007/978-1-4612-0229-5_22

Cited by 7 publications

(3 citation statements)

References 8 publications

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“…Liquid chromatography-MS or LC-MS/MS using authentic standards is widely accepted as the method of choice for the quantitation of pharmaceutical compounds (Dulik et al, 1996;Lee & Kerns, 1999). In addition, alternative quantitative techniques, such as UV (Lee et al, 2005;Loboz et al, 2005) or fluorescence detection (Fang, Semple, & Song, 2004;Wang et al, 2005b), have commonly been applied to biological analyses when standard compounds are available.…”

Section: A Drug Discoverymentioning

confidence: 99%

Analytical strategies for identifying drug metabolites

Prakash

Shaffer

Nedderman

2007

Mass Spectrometry Reviews

282

212

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With the dramatic increase in the number of new chemical entities (NCEs) arising from combinatorial chemistry and modern high-throughput bioassays, novel bioanalytical techniques are required for the rapid determination of the metabolic stability and metabolites of these NCEs. Knowledge of the metabolic site(s) of the NCEs in early drug discovery is essential for selecting compounds with favorable pharmacokinetic credentials and aiding medicinal chemists in modifying metabolic "soft spots". In development, elucidation of biotransformation pathways of a drug candidate by identifying its circulatory and excretory metabolites is vitally important to understand its physiological effects. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) have played an invaluable role in the structural characterization and quantification of drug metabolites. Indeed, liquid chromatography (LC) coupled with atmospheric pressure ionization (API) MS has now become the most powerful tool for the rapid detection, structure elucidation, and quantification of drug-derived material within various biological fluids. Often, however, MS alone is insufficient to identify the exact position of oxidation, to differentiate isomers, or to provide the precise structure of unusual and/or unstable metabolites. In addition, an excess of endogenous material in biological samples often suppress the ionization of drug-related material complicating metabolite identification by MS. In these cases, multiple analytical and wet chemistry techniques, such as LC-NMR, enzymatic hydrolysis, chemical derivatization, and hydrogen/deuterium-exchange (H/D-exchange) combined with MS are used to characterize the novel and isomeric metabolites of drug candidates. This review describes sample preparation and introduction strategies to minimize ion suppression by biological matrices for metabolite identification studies, the application of various LC-tandem MS (LC-MS/MS) techniques for the rapid quantification and identification of drug metabolites, and future trends in this field.

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Section: A Drug Discoverymentioning

confidence: 99%

Analytical strategies for identifying drug metabolites

Prakash

Shaffer

Nedderman

2007

Mass Spectrometry Reviews

282

212

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“…For the determination of metabolite profiles in complex in vivo samples, including several metabolites, application of gradient elution with long and narrow columns (100–200 mm × <2 mm i.d.) has been shown to offer good separation of the compounds 64. Owing to decreased solvent flow‐rate, increased analysis time is the disadvantage of these systems, especially when a gradient run is performed.…”

Section: Liquid Chromatography (Lc)mentioning

confidence: 99%

“…The quantitative method in metabolite analysis must be sensitive, selective, reliable, robust and fast. It is widely accepted that LC/MS fulfils these requirements 64, 101–103…”

Section: Metabolite Quantitationmentioning

confidence: 99%

Liquid chromatography/atmospheric pressure ionization–mass spectrometry in drug metabolism studies

et al. 2003

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The study of the metabolic fate of drugs is an essential and important part of the drug development process. The analysis of metabolites is a challenging task and several different analytical methods have been used in these studies. However, after the introduction of the atmospheric pressure ionization (API) technique, electrospray and atmospheric pressure chemical ionization, liquid chromatography/mass spectrometry (LC/MS) has become an important and widely used method in the analysis of metabolites owing to its superior specificity, sensitivity and efficiency. In this paper the feasibility of LC/API-MS techniques in the identification, structure characterization and quantitation of drug metabolites is reviewed. Sample preparation, LC techniques, isotope labeling, suitability of different MS techniques, such as tandem mass spectrometry, and high-resolution MS in drug metabolite analysis, are summarized and discussed. Automation of data acquisition and interpretation, special techniques and possible future trends are also the topics of the review.

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Structure elucidation of three isomeric metabolites of SYN-2836, a novel antifungal agent, in dogs via liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry methodologies

Poglod

Micetich

et al. 1999

J. Mass Spectrom.

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Applications of Tandem Liquid Chromatography/Mass Spectrometry in Drug Biotransformation and Quantification Studies

Cited by 7 publications

References 8 publications

Analytical strategies for identifying drug metabolites

Analytical strategies for identifying drug metabolites

Liquid chromatography/atmospheric pressure ionization–mass spectrometry in drug metabolism studies

Structure elucidation of three isomeric metabolites of SYN-2836, a novel antifungal agent, in dogs via liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry methodologies

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