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Quantitative metabolite profiling of an amino group containing pharmaceutical in human plasma via precolumn derivatization and high-performance liquid chromatography-inductively coupled plasma mass spectrometry

Sanwang Li UGent, Balázs Klencsár UGent, Lieve Balcaen UGent, Filip Cuyckens, Frederic Lynen UGent and Frank Vanhaecke UGent (2017) ANALYTICAL CHEMISTRY. 89(3). p.1907-1915
abstract
Quantitative determination of the candidate drug molecule and its metabolites in biofluids and tissues is an inevitable step in the development of new pharmaceuticals. Because of the time-consuming and expensive nature of the current standard technique for quantitative metabolite profiling, i.e., radiolabeling followed by high-performance liquid chromatography (HPLC) with radiodetection, the development of alternative methodologies is of great interest. In this work, a simple, fast, sensitive, and accurate method for the quantitative metabolite profiling of an amino group containing drug (levothyroxine) and its metabolites in human plasma, based on precolumn derivatization followed by HPLC-inductively coupled plasma mass spectrometry (ICPMS), was developed and validated. To introduce a suitable "heteroelement" (defined here as an element that is detectable with ICPMS), an inexpensive and commercially available reagent, tetrabromophthalic anhydride (TBPA) was used for the derivatization of free NH2-groups. The presence of a known number of I atoms in both the drug molecule and its metabolites enabled a cross-validation of the newly developed derivatization procedure and quantification based on monitoring of the introduced Br. The formation of the derivatives was quantitative, providing a 4:1 stoichiometric Br/NH2 ratio. The derivatives were separated via reversed-phase HPLC with gradient elution. Bromine was determined via ICPMS at a mass-to-charge ratio of 79 using H-2, as a reaction gas to ensure interference-free detection, and iodine was determined at a mass-to-charge ratio of 127 for cross-validation purposes. The method developed shows a fit-for-purpose accuracy (recovery between 85% and 115%) and precision (repeatability <15% RSD). The limit of quantification (LoQ) for Br was approximately 100 mu g/L.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
HPLC-ICP-MS, CONTAINING DRUG METABOLITES, ONLINE ISOTOPE-DILUTION, SOLID-PHASE EXTRACTION, CAPILLARY-ELECTROPHORESIS, CHROMIUM SPECIATION, BIOGENIC-AMINES, POLAND WATER, QUANTIFICATION, IDENTIFICATION
journal title
ANALYTICAL CHEMISTRY
Anal. Chem.
volume
89
issue
3
pages
1907 - 1915
Web of Science type
Article
Web of Science id
000393738300070
ISSN
0003-2700
1520-6882
DOI
10.1021/acs.analchem.6b04388
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8516494
handle
http://hdl.handle.net/1854/LU-8516494
date created
2017-03-31 08:22:13
date last changed
2017-07-06 07:57:33
@article{8516494,
  abstract     = {Quantitative determination of the candidate drug molecule and its metabolites in biofluids and tissues is an inevitable step in the development of new pharmaceuticals. Because of the time-consuming and expensive nature of the current standard technique for quantitative metabolite profiling, i.e., radiolabeling followed by high-performance liquid chromatography (HPLC) with radiodetection, the development of alternative methodologies is of great interest. In this work, a simple, fast, sensitive, and accurate method for the quantitative metabolite profiling of an amino group containing drug (levothyroxine) and its metabolites in human plasma, based on precolumn derivatization followed by HPLC-inductively coupled plasma mass spectrometry (ICPMS), was developed and validated. To introduce a suitable {\textacutedbl}heteroelement{\textacutedbl} (defined here as an element that is detectable with ICPMS), an inexpensive and commercially available reagent, tetrabromophthalic anhydride (TBPA) was used for the derivatization of free NH2-groups. The presence of a known number of I atoms in both the drug molecule and its metabolites enabled a cross-validation of the newly developed derivatization procedure and quantification based on monitoring of the introduced Br. The formation of the derivatives was quantitative, providing a 4:1 stoichiometric Br/NH2 ratio. The derivatives were separated via reversed-phase HPLC with gradient elution. Bromine was determined via ICPMS at a mass-to-charge ratio of 79 using H-2, as a reaction gas to ensure interference-free detection, and iodine was determined at a mass-to-charge ratio of 127 for cross-validation purposes. The method developed shows a fit-for-purpose accuracy (recovery between 85\% and 115\%) and precision (repeatability {\textlangle}15\% RSD). The limit of quantification (LoQ) for Br was approximately 100 mu g/L.},
  author       = {Li, Sanwang and Klencs{\'a}r, Bal{\'a}zs and Balcaen, Lieve and Cuyckens, Filip and Lynen, Frederic and Vanhaecke, Frank},
  issn         = {0003-2700},
  journal      = {ANALYTICAL CHEMISTRY},
  keyword      = {HPLC-ICP-MS,CONTAINING DRUG METABOLITES,ONLINE ISOTOPE-DILUTION,SOLID-PHASE EXTRACTION,CAPILLARY-ELECTROPHORESIS,CHROMIUM SPECIATION,BIOGENIC-AMINES,POLAND WATER,QUANTIFICATION,IDENTIFICATION},
  language     = {eng},
  number       = {3},
  pages        = {1907--1915},
  title        = {Quantitative metabolite profiling of an amino group containing pharmaceutical in human plasma via precolumn derivatization and high-performance liquid chromatography-inductively coupled plasma mass spectrometry},
  url          = {http://dx.doi.org/10.1021/acs.analchem.6b04388},
  volume       = {89},
  year         = {2017},
}

Chicago
Li, Sanwang, Balázs Klencsár, Lieve Balcaen, Filip Cuyckens, Frederic Lynen, and Frank Vanhaecke. 2017. “Quantitative Metabolite Profiling of an Amino Group Containing Pharmaceutical in Human Plasma via Precolumn Derivatization and High-performance Liquid Chromatography-inductively Coupled Plasma Mass Spectrometry.” Analytical Chemistry 89 (3): 1907–1915.
APA
Li, Sanwang, Klencsár, B., Balcaen, L., Cuyckens, F., Lynen, F., & Vanhaecke, F. (2017). Quantitative metabolite profiling of an amino group containing pharmaceutical in human plasma via precolumn derivatization and high-performance liquid chromatography-inductively coupled plasma mass spectrometry. ANALYTICAL CHEMISTRY, 89(3), 1907–1915.
Vancouver
1.
Li S, Klencsár B, Balcaen L, Cuyckens F, Lynen F, Vanhaecke F. Quantitative metabolite profiling of an amino group containing pharmaceutical in human plasma via precolumn derivatization and high-performance liquid chromatography-inductively coupled plasma mass spectrometry. ANALYTICAL CHEMISTRY. 2017;89(3):1907–15.
MLA
Li, Sanwang, Balázs Klencsár, Lieve Balcaen, et al. “Quantitative Metabolite Profiling of an Amino Group Containing Pharmaceutical in Human Plasma via Precolumn Derivatization and High-performance Liquid Chromatography-inductively Coupled Plasma Mass Spectrometry.” ANALYTICAL CHEMISTRY 89.3 (2017): 1907–1915. Print.