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

(2012) ANALYTICAL CHEMISTRY. 84(5). p.2395-2401
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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.
Keywords
PLASMA-MASS SPECTROMETRY, ICP-MS, LIQUID-CHROMATOGRAPHY, SPECIATION, FECES, SYSTEM

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Citation

Please use this url to cite or link to this publication:

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.
@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      = {PLASMA-MASS SPECTROMETRY,ICP-MS,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},
}

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