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

Bu, Hai‐Zhi; Poglod, Marzena; Micetich, Ronald G.; Khan, Jehangir K.

doi:10.1002/(sici)1096-9888(199911)34:11<1185::aid-jms879>3.0.co;2-r

Cited by 15 publications

(17 citation statements)

References 11 publications

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“…However, this process is usually complicated, especially for drugs undergoing extensive metabolism. In this study, SYN‐2836 metabolites were identified using various correlative strategies18 outlined as follows: (1) generation of product ion mass spectra of precursor ions preselected as possible metabolites; (2) selection of SYN‐2836‐related [M + H] + ions and elimination of non‐drug‐related species, based on the premise that metabolites of a drug preserve some of the substructures of the parent compound and therefore form some characteristic product ions corresponding to these substructures; (3) structure prediction of possible metabolites in terms of known biotransformation pathways; (4) preassignment of the predicted structures to the selected [M + H] + ions based on their equivalence in molecular weights; (5) acceptance or rejection of the preassigned metabolite structures by interpretation of their product ion spectra; (6) structure postulation of SYN‐2836‐related [M + H] + ions without predicted structures by mass spectral interpretation guided by knowledge of related substructures and known metabolites; and (7) structure postulation of metabolites formed by complex or irregular metabolic reactions using complementary approaches. In addition, correlation analysis of product ion mass spectra and chromatographic behavior between corresponding metabolites of SYN‐2836 and SYN‐2869,18 providing a radiolabel‐like tracking, as well as the nitrogen rule,20 were also employed for the identification of the selected SYN‐2836 metabolites.…”

Section: Resultsmentioning

confidence: 99%

“…It has been observed that this agent undergoes extensive metabolism in beagle dogs following oral administration 16. Previously, three isomeric metabolites (M3, M4 and M5), and their two precursor metabolites (M1 and M2) of SYN‐2836, have been identified using LC/MS/MS methodologies 18. As a continuation, this report presents the structural elucidation of other SYN‐2836 metabolites.…”

mentioning

confidence: 75%

“…Administration of SYN‐2836 and SYN‐2869 to the male beagle dogs, and the subsequent urine collection, were performed as in our previous report 18…”

Section: Methodsmentioning

confidence: 99%

“…A Micromass Quattro II triple quadrupole mass spectrometer (Manchester, UK) was used for mass spectrometric analysis. All other conditions were the same as in our previous report 18…”

Section: Methodsmentioning

confidence: 99%

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Practical aspects of liquid chromatography/electrospray tandem mass spectrometry for rapid identification of metabolites of a new antifungal agent SYN‐2836 in dog urine

Poglod

Micetich

et al. 2001

Rapid Comm Mass Spectrometry

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This report presents the structural elucidation of 12 urinary metabolites of SYN-2836, a new antifungal agent showing extensive metabolism in beagle dogs, using complementary liquid chromatography/tandem mass spectrometry (LC/MS/MS) methodologies. The 12 SYN-2836 metabolites were readily divided into four groups by considering that all three members of each group, although differing in masses, exhibited highly similar product ion mass spectra. This suggests that the metabolites within each group share a common major substructure. Therefore, all the grouped SYN-2836 metabolites were strategically identified by characterization of the major substructures followed by determination of the additional small substructures. This grouping strategy greatly facilitated the structural elucidation of these metabolites. Other strategies were also employed to achieve as rapid and unambiguous characterization of the SYN-2836 metabolites as possible.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 75%

“…Administration of SYN‐2836 and SYN‐2869 to the male beagle dogs, and the subsequent urine collection, were performed as in our previous report 18…”

Section: Methodsmentioning

confidence: 99%

“…A Micromass Quattro II triple quadrupole mass spectrometer (Manchester, UK) was used for mass spectrometric analysis. All other conditions were the same as in our previous report 18…”

Section: Methodsmentioning

confidence: 99%

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Practical aspects of liquid chromatography/electrospray tandem mass spectrometry for rapid identification of metabolites of a new antifungal agent SYN‐2836 in dog urine

Poglod

Micetich

et al. 2001

Rapid Comm Mass Spectrometry

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“…This information can be obtained from databases based on published in vitro and in vivo biotransformation routes of compounds [90]. Zhang et al, [38] developed a rapid method for metabolite identification using Time-of Flight (TOF) LC-MS. Ferna'ndez-Metzler et al, [39] and Lim et al [40], Bu et al, [41] used fast LC-MS and LC-MS-MS, respectively, to identify metabolites. van Breemen et al [42] developed a HTS pulsed ultrafiltration mass spectrometry method for the in vitro formation and characterization of microsomal drug metabolites.…”

Section: Metabolite Identificationmentioning

confidence: 99%

In Vitro High Throughput Screening of Compounds for Favorable Metabolic Properties in Drug Discovery.

Masimirembwa¹,

Thompson²,

Andersson

2001

CCHTS

108

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Drug metabolism can have profound effects on the pharmacological and toxicological profile of therapeutic agents. In the pharmaceutical industry, many in vitro techniques are in place or under development to screen and optimize compounds for favorable metabolic properties in the drug discovery phase. These in vitro technologies are meant to address important issues such as: (1) is the compound a potent inhibitor of drug metabolising enzymes (DMEs)? (2) does the compound induce the expression of DMEs? (3) how labile is the compound to metabolic degradation? (4) which specific enzyme(s) is responsible for the compound's biotransformation? and (5) to which metabolites is the compound metabolized? Answers to these questions provide a basis for judging whether a compound is likely to have acceptable pharmacokinetic properties in vivo. To address these issues on the increasing number of compounds inundating the drug discovery programs, high throughput assays are essential. A combination of biochemical advances in the understanding of the function and regulation of DMEs (in particular, cytochromes P450, CYPs) and automated analytical technologies are revolutionizing drug metabolism research. Automated LC-MS based metabolic stability, fluorescence, radiometric and LC-MS based CYP inhibition assays are now in routine use. Automatible models for studying CYP induction based on enzyme activity, quantitative RT-PCR and reporter gene systems are being developed. We will review the utility and limitations of these HTS approaches and highlight on-going developments and emerging technologies to answer metabolism questions at the different stages of the drug discovery process.

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Liquid chromatography-mass spectrometry in the study of the metabolism of drugs and other xenobiotics

Oliveira

Watson

2000

Biomed. Chromatogr.

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The application of liquid chromatography-mass spectrometry (LC/MS) to the study of metabolism of drugs and other xenobiotics is reviewed. Original research papers covering the period from 1998 to early 2000 and concerning the use of LC/MS in the study of xenobiotic metabolism in humans and other mammalian species are reviewed. LC/MS interfaces, sample preparation steps, column types, mobile phases and additives, and the type of metabolites detected are summarized and discussed in an attempt to identify the current and future trends in the use of LC/MS for metabolism studies. Applications are listed according to the parent xenobiotic type and include substances used in therapeutics, drug candidates, compounds being evaluated in clinical trials, environmental pollutants, adulterants and naturally occurring substances.

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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

Cited by 15 publications

References 11 publications

Practical aspects of liquid chromatography/electrospray tandem mass spectrometry for rapid identification of metabolites of a new antifungal agent SYN‐2836 in dog urine

Practical aspects of liquid chromatography/electrospray tandem mass spectrometry for rapid identification of metabolites of a new antifungal agent SYN‐2836 in dog urine

In Vitro High Throughput Screening of Compounds for Favorable Metabolic Properties in Drug Discovery.

Liquid chromatography-mass spectrometry in the study of the metabolism of drugs and other xenobiotics

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