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HPLC/ICP-MS in combination with 'reverse' online isotope dilution in drug metabolism studies

Björn Meermann UGent, Anne Hulstaert UGent, Aline Laenen, Cis Van Looveren, Maarten Vliegen, Filip Cuyckens and Frank Vanhaecke UGent (2012) ANALYTICAL CHEMISTRY. 84(5). p.2395-2401
abstract
During the development of a new drug compound, its metabolism needs to be unraveled. For quantification of the metabolites formed, the drug under investigation is traditionally synthesized with a radiolabel (C-14 or H-3) and the metabolites present in different matrixes (blood, urine, feces) upon drug administration are determined by means of high-performance liquid chromatography (HPLC) coupled to radiodetection. This approach allows for quantification of the metabolites formed and enables a straightforward distinction between exogenous (i.e., drug-related) and endogenous species (as only the radiolabeled species are detected). However, in some cases, the use of a radiolabeled compound in human in vivo studies is not advisible, e.g., for drug compounds or their metabolites showing a long plasma or tissue half-life. In cases where the candidate drug molecule contains an element detectable by means of inductively coupled plasma mass spectrometry (ICP-MS), HPLC/ICP-MS is a promising alternative approach. However, the method lacks specificity when a distinction between drug-related species and endogenous compounds containing the same target element needs to be accomplished. As a result, we have developed an HPLC/ICP-MS-based method combined with "reverse" online isotope dilution ("reverse" online ID) for metabolite quantification. The methodology was evaluated by the analysis of feces samples from rats dosed with a Br-81-labeled drug compound. The method allows for both (i) valid quantification of the drug metabolites and (ii) distinction among endogenous, exogenous, and "mixed" species, based on their isotopic "fingerprint". A good repeatability (relative standard deviation of 4.2%) and limit of detection (0.35 mg of drug compound L-1 of feces extract), of the same order of magnitude as those observed for "normal" online ID HPLC/ICP-MS and HPLC/radiodetection, were achieved.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ICP-MS, PLASMA-MASS SPECTROMETRY, LIQUID-CHROMATOGRAPHY, SPECIATION, FECES, SYSTEM
journal title
ANALYTICAL CHEMISTRY
Anal. Chem.
volume
84
issue
5
pages
2395 - 2401
Web of Science type
Article
Web of Science id
000301021400043
JCR category
CHEMISTRY, ANALYTICAL
JCR impact factor
5.695 (2012)
JCR rank
3/74 (2012)
JCR quartile
1 (2012)
ISSN
0003-2700
DOI
10.1021/ac203165p
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2084614
handle
http://hdl.handle.net/1854/LU-2084614
date created
2012-04-12 10:09:20
date last changed
2012-04-12 13:05:44
@article{2084614,
  abstract     = {During the development of a new drug compound, its metabolism needs to be unraveled. For quantification of the metabolites formed, the drug under investigation is traditionally synthesized with a radiolabel (C-14 or H-3) and the metabolites present in different matrixes (blood, urine, feces) upon drug administration are determined by means of high-performance liquid chromatography (HPLC) coupled to radiodetection. This approach allows for quantification of the metabolites formed and enables a straightforward distinction between exogenous (i.e., drug-related) and endogenous species (as only the radiolabeled species are detected). However, in some cases, the use of a radiolabeled compound in human in vivo studies is not advisible, e.g., for drug compounds or their metabolites showing a long plasma or tissue half-life. In cases where the candidate drug molecule contains an element detectable by means of inductively coupled plasma mass spectrometry (ICP-MS), HPLC/ICP-MS is a promising alternative approach. However, the method lacks specificity when a distinction between drug-related species and endogenous compounds containing the same target element needs to be accomplished. As a result, we have developed an HPLC/ICP-MS-based method combined with {\textacutedbl}reverse{\textacutedbl} online isotope dilution ({\textacutedbl}reverse{\textacutedbl} online ID) for metabolite quantification. The methodology was evaluated by the analysis of feces samples from rats dosed with a Br-81-labeled drug compound. The method allows for both (i) valid quantification of the drug metabolites and (ii) distinction among endogenous, exogenous, and {\textacutedbl}mixed{\textacutedbl} species, based on their isotopic {\textacutedbl}fingerprint{\textacutedbl}. A good repeatability (relative standard deviation of 4.2\%) and limit of detection (0.35 mg of drug compound L-1 of feces extract), of the same order of magnitude as those observed for {\textacutedbl}normal{\textacutedbl} online ID HPLC/ICP-MS and HPLC/radiodetection, were achieved.},
  author       = {Meermann, Bj{\"o}rn and Hulstaert, Anne and Laenen, Aline and Van Looveren, Cis and Vliegen, Maarten and Cuyckens, Filip and Vanhaecke, Frank},
  issn         = {0003-2700},
  journal      = {ANALYTICAL CHEMISTRY},
  keyword      = {ICP-MS,PLASMA-MASS SPECTROMETRY,LIQUID-CHROMATOGRAPHY,SPECIATION,FECES,SYSTEM},
  language     = {eng},
  number       = {5},
  pages        = {2395--2401},
  title        = {HPLC/ICP-MS in combination with 'reverse' online isotope dilution in drug metabolism studies},
  url          = {http://dx.doi.org/10.1021/ac203165p},
  volume       = {84},
  year         = {2012},
}

Chicago
Meermann, Björn, Anne Hulstaert, Aline Laenen, Cis Van Looveren, Maarten Vliegen, Filip Cuyckens, and Frank Vanhaecke. 2012. “HPLC/ICP-MS in Combination with ‘Reverse’ Online Isotope Dilution in Drug Metabolism Studies.” Analytical Chemistry 84 (5): 2395–2401.
APA
Meermann, B., Hulstaert, A., Laenen, A., Van Looveren, C., Vliegen, M., Cuyckens, F., & Vanhaecke, F. (2012). HPLC/ICP-MS in combination with “reverse” online isotope dilution in drug metabolism studies. ANALYTICAL CHEMISTRY, 84(5), 2395–2401.
Vancouver
1.
Meermann B, Hulstaert A, Laenen A, Van Looveren C, Vliegen M, Cuyckens F, et al. HPLC/ICP-MS in combination with “reverse” online isotope dilution in drug metabolism studies. ANALYTICAL CHEMISTRY. 2012;84(5):2395–401.
MLA
Meermann, Björn, Anne Hulstaert, Aline Laenen, et al. “HPLC/ICP-MS in Combination with ‘Reverse’ Online Isotope Dilution in Drug Metabolism Studies.” ANALYTICAL CHEMISTRY 84.5 (2012): 2395–2401. Print.