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A comparison between HPLC-dynamic reaction cell-ICP-MS and HPLC-sector field-ICP-MS for the detection of glutathione-trapped reactive drug metabolites using clozapine as a model compound

Kenny De Wolf UGent, Lieve Balcaen UGent, Elke Van De Walle UGent, Filip Cuyckens and Frank Vanhaecke UGent (2010) JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY. 25(3). p.419-425
abstract
In this study, a novel method was developed for tracing down reactive drug metabolites, the formation of which in the human body constitutes an important health risk as a result of their capability to bind to body proteins and DNA. Clozapine was used as a model because this drug forms both reactive and stable metabolites. Glutathione, which forms complexes with reactive metabolites, was added in order to trap reactive species of clozapine, formed by degradation in an electrochemical cell, thereby mimicking the real drug metabolism process. The method developed is based on the use of reversed-phase HPLC as a chromatographic separation technique and inductively coupled plasma-mass spectrometry (ICP-MS) for monitoring of Cl and S. Via Cl-monitoring, all metabolites of the Cl-containing clozapine can be detected, whereas S-monitoring allows for the detection of the S-containing molecule glutathione and its conjugates with reactive metabolites. The spectral overlap of the signals of S-32(+) and S-34(+) with those of (OO+)-O-16-O-16 and (OO+)-O-16-O-18, respectively, was tackled in 2 ways. On one hand, a quadrupole-based ICP-MS instrument, equipped with a dynamic reaction cell, was used. O-2 was used as a reaction gas to convert the S+ ions to a sufficient extent into the corresponding SO+ species. This did not yield optimal results, due to pronounced ArC+ signals at mass 48 and 50 upon introduction of methanol into the ICP. On the other hand, a sector-field ICP-MS instrument operated at medium mass resolution permitted interference-free monitoring of the S+-signals. A new type of skimmer cone - termed X-skimmer - was evaluated and its use resulted in a 4-fold increase in the sensitivity in a methanolic environment, providing a limit of detection of 1 mu g L-1 for S. The chromatograms obtained via HPLC-SF-ICP-MS permitted differentiation between reactive and stable metabolites. As a result, the method developed looks very promising for the detection of glutathione conjugates and shows potential for their quantification in early stages of drug development when a radiolabeled compound is not yet available.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
QUANTITATIVE PROTEIN-ANALYSIS, ELEMENT, PLASMA-MASS SPECTROMETRY, ISOTOPE-DILUTION TECHNIQUE, SULFUR-SPECIFIC DETECTION, ACCURATE DETERMINATION, IN-VITRO, AGRANULOCYTOSIS, CHROMATOGRAPHY, RESOLUTION
journal title
JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY
J. Anal. At. Spectrom.
volume
25
issue
3
pages
7 pages
Web of Science type
Article
Web of Science id
000274961600022
JCR category
CHEMISTRY, ANALYTICAL
JCR impact factor
4.372 (2010)
JCR rank
5/71 (2010)
JCR quartile
1 (2010)
ISSN
0267-9477
DOI
10.1039/b921638c
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
933787
handle
http://hdl.handle.net/1854/LU-933787
date created
2010-04-20 16:32:22
date last changed
2010-04-28 14:23:18
@article{933787,
  abstract     = {In this study, a novel method was developed for tracing down reactive drug metabolites, the formation of which in the human body constitutes an important health risk as a result of their capability to bind to body proteins and DNA. Clozapine was used as a model because this drug forms both reactive and stable metabolites. Glutathione, which forms complexes with reactive metabolites, was added in order to trap reactive species of clozapine, formed by degradation in an electrochemical cell, thereby mimicking the real drug metabolism process. The method developed is based on the use of reversed-phase HPLC as a chromatographic separation technique and inductively coupled plasma-mass spectrometry (ICP-MS) for monitoring of Cl and S. Via Cl-monitoring, all metabolites of the Cl-containing clozapine can be detected, whereas S-monitoring allows for the detection of the S-containing molecule glutathione and its conjugates with reactive metabolites. The spectral overlap of the signals of S-32(+) and S-34(+) with those of (OO+)-O-16-O-16 and (OO+)-O-16-O-18, respectively, was tackled in 2 ways. On one hand, a quadrupole-based ICP-MS instrument, equipped with a dynamic reaction cell, was used. O-2 was used as a reaction gas to convert the S+ ions to a sufficient extent into the corresponding SO+ species. This did not yield optimal results, due to pronounced ArC+ signals at mass 48 and 50 upon introduction of methanol into the ICP. On the other hand, a sector-field ICP-MS instrument operated at medium mass resolution permitted interference-free monitoring of the S+-signals. A new type of skimmer cone - termed X-skimmer - was evaluated and its use resulted in a 4-fold increase in the sensitivity in a methanolic environment, providing a limit of detection of 1 mu g L-1 for S. The chromatograms obtained via HPLC-SF-ICP-MS permitted differentiation between reactive and stable metabolites. As a result, the method developed looks very promising for the detection of glutathione conjugates and shows potential for their quantification in early stages of drug development when a radiolabeled compound is not yet available.},
  author       = {De Wolf, Kenny and Balcaen, Lieve and Van De Walle, Elke and Cuyckens, Filip and Vanhaecke, Frank},
  issn         = {0267-9477},
  journal      = {JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY},
  keyword      = {QUANTITATIVE PROTEIN-ANALYSIS,ELEMENT,PLASMA-MASS SPECTROMETRY,ISOTOPE-DILUTION TECHNIQUE,SULFUR-SPECIFIC DETECTION,ACCURATE DETERMINATION,IN-VITRO,AGRANULOCYTOSIS,CHROMATOGRAPHY,RESOLUTION},
  language     = {eng},
  number       = {3},
  pages        = {419--425},
  title        = {A comparison between HPLC-dynamic reaction cell-ICP-MS and HPLC-sector field-ICP-MS for the detection of glutathione-trapped reactive drug metabolites using clozapine as a model compound},
  url          = {http://dx.doi.org/10.1039/b921638c},
  volume       = {25},
  year         = {2010},
}

Chicago
De Wolf, Kenny, Lieve Balcaen, Elke Van De Walle, Filip Cuyckens, and Frank Vanhaecke. 2010. “A Comparison Between HPLC-dynamic Reaction cell-ICP-MS and HPLC-sector field-ICP-MS for the Detection of Glutathione-trapped Reactive Drug Metabolites Using Clozapine as a Model Compound.” Journal of Analytical Atomic Spectrometry 25 (3): 419–425.
APA
De Wolf, Kenny, Balcaen, L., Van De Walle, E., Cuyckens, F., & Vanhaecke, F. (2010). A comparison between HPLC-dynamic reaction cell-ICP-MS and HPLC-sector field-ICP-MS for the detection of glutathione-trapped reactive drug metabolites using clozapine as a model compound. JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY, 25(3), 419–425.
Vancouver
1.
De Wolf K, Balcaen L, Van De Walle E, Cuyckens F, Vanhaecke F. A comparison between HPLC-dynamic reaction cell-ICP-MS and HPLC-sector field-ICP-MS for the detection of glutathione-trapped reactive drug metabolites using clozapine as a model compound. JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY. 2010;25(3):419–25.
MLA
De Wolf, Kenny, Lieve Balcaen, Elke Van De Walle, et al. “A Comparison Between HPLC-dynamic Reaction cell-ICP-MS and HPLC-sector field-ICP-MS for the Detection of Glutathione-trapped Reactive Drug Metabolites Using Clozapine as a Model Compound.” JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY 25.3 (2010): 419–425. Print.