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A pre-column derivatization method allowing quantitative metabolite profiling of carboxyl and phenolic hydroxyl group containing pharmaceuticals in human plasma via liquid chromatography-inductively coupled plasma-tandem mass spectrometry (LC-ICP-MS/MS)

Sanwang Li (UGent) , Balázs Klencsár (UGent) , Lieve Balcaen (UGent) , Filip Cuyckens, Frederic Lynen (UGent) and Frank Vanhaecke (UGent)
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Abstract
The development of suitable analytical methods for drug ADME (absorption, distribution, metabolism and excretion) studies is of great importance. The currently routinely applied detection techniques usually demonstrate a structure-dependent analytical response (MS-based method) or require the synthesis of a radiolabelled version of the parent drug (radiodetection) for accurate quantification. Inductively coupled plasma-(tandem) mass spectrometry (ICP-MS(/MS)) offers a promising alternative to radiolabelling followed by radiodetection due to the structure-independent nature of its analytical response. Within the context of this study, an accurate, simple and sensitive HPLC-ICP-MS/MS method for the quantitative metabolite profiling of diclofenac in human plasma based on the pre-column derivatization of the carboxylic and phenolic -OH groups present in the parent drug and its major metabolite, 4'-hydroxy-diclofenac, was developed and validated. A cost-effective and commercially available derivatization reagent, p-bromophenacyl bromide (p-BPB), was applied for the introduction of Br into the drug molecule and its major metabolite, enabling the element-selective detection and quantification based on the Br-signal. The presence of Cl in both diclofenac and 4'-hydroxy-diclofenac allowed an additional validation via simultaneous monitoring of the Cl-signal by using a state-of-art ICP-MS/MS instrument equipped with a collision/reaction cell. The reaction conditions were successfully optimized to achieve a quantitative formation of the corresponding derivatization products, while the baseline separation of the target compounds in a typical biological matrix (i.e. human plasma) was achieved using gradient reversed phase high-performance liquid chromatography (RP-HPLC). A fit-for-purpose accuracy (recovery between 85-115%) and precision (repeatability <= 7.2% RSD) were achieved. The limits of quantification (LOQ) are approximate to 50 mu g L-1 for Br and approximate to 80 mu g L-1 for Cl, corresponding to approximate to 0.2 mg L-1 and approximate to 0.4 mg L-1 of diclofenac, respectively.
Keywords
CONTAINING DRUG METABOLITES, ONLINE ISOTOPE-DILUTION, IN-VIVO, HPLC/ICP-MS, NMR-SPECTROSCOPY, ESI-MS, QUANTIFICATION, PHOSPHORUS, ACIDS, IDENTIFICATION

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Chicago
Li, Sanwang, Balázs Klencsár, Lieve Balcaen, Filip Cuyckens, Frederic Lynen, and Frank Vanhaecke. 2018. “A Pre-column Derivatization Method Allowing Quantitative Metabolite Profiling of Carboxyl and Phenolic Hydroxyl Group Containing Pharmaceuticals in Human Plasma via Liquid Chromatography-inductively Coupled Plasma-tandem Mass Spectrometry (LC-ICP-MS/MS).” Journal of Analytical Atomic Spectrometry 33 (2): 274–282.
APA
Li, Sanwang, Klencsár, B., Balcaen, L., Cuyckens, F., Lynen, F., & Vanhaecke, F. (2018). A pre-column derivatization method allowing quantitative metabolite profiling of carboxyl and phenolic hydroxyl group containing pharmaceuticals in human plasma via liquid chromatography-inductively coupled plasma-tandem mass spectrometry (LC-ICP-MS/MS). JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY, 33(2), 274–282.
Vancouver
1.
Li S, Klencsár B, Balcaen L, Cuyckens F, Lynen F, Vanhaecke F. A pre-column derivatization method allowing quantitative metabolite profiling of carboxyl and phenolic hydroxyl group containing pharmaceuticals in human plasma via liquid chromatography-inductively coupled plasma-tandem mass spectrometry (LC-ICP-MS/MS). JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY. 2018;33(2):274–82.
MLA
Li, Sanwang, Balázs Klencsár, Lieve Balcaen, et al. “A Pre-column Derivatization Method Allowing Quantitative Metabolite Profiling of Carboxyl and Phenolic Hydroxyl Group Containing Pharmaceuticals in Human Plasma via Liquid Chromatography-inductively Coupled Plasma-tandem Mass Spectrometry (LC-ICP-MS/MS).” JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY 33.2 (2018): 274–282. Print.
@article{8556664,
  abstract     = {The development of suitable analytical methods for drug ADME (absorption, distribution, metabolism and excretion) studies is of great importance. The currently routinely applied detection techniques usually demonstrate a structure-dependent analytical response (MS-based method) or require the synthesis of a radiolabelled version of the parent drug (radiodetection) for accurate quantification. Inductively coupled plasma-(tandem) mass spectrometry (ICP-MS(/MS)) offers a promising alternative to radiolabelling followed by radiodetection due to the structure-independent nature of its analytical response. Within the context of this study, an accurate, simple and sensitive HPLC-ICP-MS/MS method for the quantitative metabolite profiling of diclofenac in human plasma based on the pre-column derivatization of the carboxylic and phenolic -OH groups present in the parent drug and its major metabolite, 4'-hydroxy-diclofenac, was developed and validated. A cost-effective and commercially available derivatization reagent, p-bromophenacyl bromide (p-BPB), was applied for the introduction of Br into the drug molecule and its major metabolite, enabling the element-selective detection and quantification based on the Br-signal. The presence of Cl in both diclofenac and 4'-hydroxy-diclofenac allowed an additional validation via simultaneous monitoring of the Cl-signal by using a state-of-art ICP-MS/MS instrument equipped with a collision/reaction cell. The reaction conditions were successfully optimized to achieve a quantitative formation of the corresponding derivatization products, while the baseline separation of the target compounds in a typical biological matrix (i.e. human plasma) was achieved using gradient reversed phase high-performance liquid chromatography (RP-HPLC). A fit-for-purpose accuracy (recovery between 85-115\%) and precision (repeatability {\textlangle}= 7.2\% RSD) were achieved. The limits of quantification (LOQ) are approximate to 50 mu g L-1 for Br and approximate to 80 mu g L-1 for Cl, corresponding to approximate to 0.2 mg L-1 and approximate to 0.4 mg L-1 of diclofenac, respectively.},
  author       = {Li, Sanwang and Klencs{\'a}r, Bal{\'a}zs and Balcaen, Lieve and Cuyckens, Filip and Lynen, Frederic and Vanhaecke, Frank},
  issn         = {0267-9477},
  journal      = {JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY},
  language     = {eng},
  number       = {2},
  pages        = {274--282},
  title        = {A pre-column derivatization method allowing quantitative metabolite profiling of carboxyl and phenolic hydroxyl group containing pharmaceuticals in human plasma via liquid chromatography-inductively coupled plasma-tandem mass spectrometry (LC-ICP-MS/MS)},
  url          = {http://dx.doi.org/10.1039/c7ja00385d},
  volume       = {33},
  year         = {2018},
}

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