Hyphenation of reverse-phase HPLC and ICP-MS for metabolite profiling—application to a novel antituberculosis compound as a case study

Balcaen, Lieve; Samber, Björn De; Wolf, Kenny De; Cuyckens, Filip; Vanhaecke, Frank

doi:10.1007/s00216-007-1303-2

Cited by 33 publications

(18 citation statements)

References 20 publications

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“…Furthermore, a "reverse" on-line isotope dilution approach (the drug is isotopically enriched in 81 Br while the spike contains natural bromine) was applied by the same group, which additionally offers the possibility to distinguish between potentially present endogenous (matrix) and exogenous (drug-related) bromine species [126]. The quantitative data obtained were in good accordance with those acquired by means of classical radioactivity detection [127]. This emphasizes the high potential of ICP-MS detection as an additional technique within clinical studies of drugs containing elements that are detectable by means of ICP-MS.…”

Section: Brominesupporting

confidence: 66%

Hyphenated techniques as tools for speciation analysis of metal-based pharmaceuticals: developments and applications

Meermann

Sperling

2012

Anal Bioanal Chem

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Method development and applications of hyphenated techniques as tools for speciation analysis of metal-based pharmaceuticals are summarized within this review. Advantages and limitations of the separation modes-high-performance liquid chromatography (HPLC), capillary electrophoresis (CE), and gas chromatography (GC)-as well as the detection modes-inductively coupled plasma-mass spectrometry (ICP-MS) and electrospray ionization-mass spectrometry (ESI-MS)-are discussed. ICP-MS detection is found to be advantageous for the quantification of drugs containing metals and other heteroatoms. The species-independent sensitivity and multielement capabilities of ICP-MS allow it to be used for quantification even when species-specific standards are not available, as well as to determine the stoichiometry in metallodrug-biomolecule interactions. Molecular information that is totally destroyed when ICP is applied as ionization source and is therefore not obtainable via ICP-MS detection can be accessed by the complementary technique of ESI-MS. Speciation analysis combining both elemental and molecular information is therefore a powerful tool for the analysis of metal-based pharmaceuticals and their metabolites in body fluids and other relevant matrices.

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Section: Brominesupporting

confidence: 66%

Hyphenated techniques as tools for speciation analysis of metal-based pharmaceuticals: developments and applications

Meermann

Sperling

2012

Anal Bioanal Chem

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“…The two ICP-MS methods described earlier used liquid-liquid extraction and solid-phase extraction and were specifically designed for metabolite profiling and not for PK monitoring (9,10). The run time is very short since the retention time of bedaquiline is 1.9 min.…”

Section: Discussionmentioning

confidence: 99%

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Alffenaar

Bolhuis

Hateren

et al. 2015

Antimicrob Agents Chemother

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dBedaquiline, a diarylquinoline for the treatment of multidrug-resistant tuberculosis (TB), relies on exposure-dependent killing. As data on drug exposure in specific populations are scarce, pharmacokinetic studies may be of interest. No simple and robust validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported to date. Therefore, a new method using a quadrupole mass spectrometer was developed for analysis of bedaquiline and N-monodesmethyl bedaquiline (M2) in human serum, using deuterated bedaquiline as the internal standard. The calibration curve was linear over a range of 0.05 (lower limit of quantification [LLOQ]) to 6.00 mg/liter for both bedaquiline and M2, with correlation coefficient values of 0.997 and 0.999, respectively. The calculated accuracy ranged from 1.9% to 13.6% for bedaquiline and 2.9% to 8.5% for M2. Within-run precision ranged from 3.0% to 7.2% for bedaquiline and 3.1% to 5.2% for M2, and between-run precision ranged from 0.0% to 4.3% for bedaquiline and 0.0% to 4.6% for M2. Evaluation of serum concentrations in a patient receiving bedaquiline showed high levels at the end of treatment, reflecting accumulation of the drug. More observational pharmacokinetic data are needed to relate altered drug concentrations to clinical outcome or adverse drug effects. A simple LC-MS/MS method to quantify bedaquiline and M2 levels in human serum using a deuterated internal standard has been validated. This method can be used in clinical studies and daily practice. Bedaquiline is a diarylquinoline and was approved by the United States Food and Drug Administration (FDA) in 2012 under the accelerated-approval program. This drug is indicated for treatment of multidrug-resistant pulmonary tuberculosis (MDR-TB) in combination with other active anti-TB drugs in adults without other treatment options (1). This new anti-TB drug, formally known as TMC207, showed exposure-dependent killing of Mycobacterium tuberculosis (2, 3). The drug is metabolized by cytochrome P 450 enzyme 3A4 (CYP3A4) to its 5-foldless-active metabolite N-monodesmethyl bedaquiline (M2) (4).Bedaquiline therapy is started in a loading dose of 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks. This dosing regimen was chosen because pharmacokinetics (PK) modeling predicted gradual accumulation in plasma and tissues (4).At this time, little data on PK in patients with advanced MDR-TB or suffering from comorbidities are available apart from the data that were collected in the clinical studies (4). However, variability in the PK of antituberculosis drugs is considerable and altered drug exposure may translate to variations in clinical outcomes (5, 6). Clearly, there is a need for more-descriptive (population) PK studies on bedaquiline to determine predictors of exposure, drug-drug interaction (7), and PK-pharmacodynamics (PD) relationships. The World Health Organization has released a guide for the use of bedaquiline and encourages additional evaluation of this new drug (8).As bedaquilin...

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“…The major isotope of sulfur 32 S (abundance 95.0 %) is interfered mainly by the polyatomic ion 16 O 16 O + which compromises importantly the sensitivity for 32 S detection. Improved responses could be obtained using sector field instruments which operate at higher mass resolution, which was not available with current instrument [19].…”

Section: Optimization Of the Icp/ms Conditions For Sulfur Detectionmentioning

confidence: 99%

“…LC-ICP/MS technology could represent an advantage in drug metabolism studies due to its ability to perform mass balance studies without radiolabeling compounds with 14 C and 3 H and may be considered as an alternative to expensive techniques such as accelerated mass spectrometry. Thus, the combination of LC and ICP/MS has been recently introduced as a promising technique for the analysis of drug compounds and their metabolites containing an element detectable by ICP/MS such as sulfur [6][7][8][9], phosphorus [10,11], chlorine [6], iodine [7,12], and bromine [3,[13][14][15][16][17][18]. Among them, sulfur is one of the most interesting elements in terms of potential application of LC-ICP/MS to drug metabolism studies.…”

Section: Introductionmentioning

confidence: 99%

Determination of S-containing drug metabolites from in vitro and in vivo metabolism studies by using LC-ICP/MS

et al. 2012

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Recently, liquid chromatography coupled to inductively coupled plasma mass spectrometry (LC-ICP/MS) has been introduced to deal with some applications in the field of pharmaceutical, biomedical, and clinical analysis. In the case of drug research, the number of drugs and their metabolites containing detectable elements is quite limited. In this paper, LC-ICP/MS has been demonstrated to be suitable for the determination of S-containing drugs and their metabolites. In order to minimize the interference of polyatomic oxygen (m/z 32), the indirect detection of S, by means of the SO(+) ion (m/z 48), was optimized. For quantification purposes, it has been encountered that the percentage of organic solvent in the mobile phase strongly affects the sensitivity. Here, corrective strategies based on calibration curves established at different solvent concentrations (solvent-zone quantification) and post-column gradient compensation have been proposed to circumvent sensitivity variations. Results obtained have shown that suitable calibration models have been built for any compound regardless of the solvent percentage at which it is eluted from the chromatographic column. To prove the applicability of this methodology, the metabolism of ethacrynic acid and tiotropium bromide has been studied in vitro and in vivo. In the first case, ethacrynic acid does not contain S in its structure, however, the major route of metabolism for this compound consists of the formation of glutathione adduct and its further degradation. In the second case, tiotropium bromide contains two S atoms in its structure.

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Hyphenation of reverse-phase HPLC and ICP-MS for metabolite profiling—application to a novel antituberculosis compound as a case study

Cited by 33 publications

References 20 publications

Hyphenated techniques as tools for speciation analysis of metal-based pharmaceuticals: developments and applications

Hyphenated techniques as tools for speciation analysis of metal-based pharmaceuticals: developments and applications

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Determination of S-containing drug metabolites from in vitro and in vivo metabolism studies by using LC-ICP/MS

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