Rapid determination of gefitinib and its main metabolite, O-desmethyl gefitinib in human plasma using liquid chromatography–tandem mass spectrometry

Wang, Lingzhi; Lim, Michelle Yi-Xiu; Chin, Tan-Min; Thuya, Win-Lwin; Nye, Pei-Ling; Wong, Andrea Li‐Ann; Chan, Sui Yung; Goh, Boon-Cher; Ho, Paul C.

doi:10.1016/j.jchromb.2011.05.056

Cited by 31 publications

(14 citation statements)

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“…The resulting chromatograms of samples shown in Figure 4 indicated that using 10% TCA as the precipitant yielded the best analyte signal intensity. Even though it has been shown that acetonitrile can efficiently remove high amounts of protein [29], it resulted in poor recovery, mass signal suppression and shifting the retention time in our experiments. Hence, 10% TCA was optimized as the protein precipitant throughout this LC-MS/MS method development and validation procedure.…”

Section: Research Article | Damavandi Chan Kraus Ho and Kangmentioning

confidence: 70%

Development of an UPLC–MS/MS Method for Assaying The Enzymatic Activity of Propionyl Coenzyme-A Carboxylase

et al. 2014

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Propionic acidemia (PA) is a rare and life threatening metabolic disorder caused by deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC). PCC is required for the catabolism of metabolites that arise from the normal turnover of several essential amino acids (e.g., methionine, isoleucine, valine and threonine) and odd chain fatty acids [1,2]. Specifically, PCC catalyzes the carboxylation of the metabolic intermediate propionyl coenzyme-A (PP-COA) to methyl malonyl coenzyme-A (MM-COA) in the matrix of mitochondria (Figure 1) [3]. The native PCC holoenzyme comprises six a and six b subunits [4]. Studies on the biochemical aspects of PCC have shown that PA can occur in patients that have mutations in one or both genes coding for the PCCa and PCCb subunits [1].The deficiency of PCC and the subsequent accumulation of PP-COA lead to the pathogenesis of PA. The most common clinical manifestations of PA include high anion-gap metabolic acidosis, ketonuria and hyperammonemia, which are frequently of sufficient severity to result in neonatal death [3]. Moreover, increased organic acids in the urine, elevated plasma glycine levels, and the characteristic increase in propionylcarnitine (C3) levels are also observed in PA patients. Therefore, detection of the accumulation of propionic acid and other related metabolites forms the basis for the initial screening and examination of patients with suspected PA. In Background: Propionyl coenzyme-A carboxylase (PCC) is a mitochondrial enzyme previously quantifiable only by radiometric assay. Herein, we report a UPLC-MS/MS method as a superior alternative method for assaying PCC's activity. Methodology & Results: For the development of the UPLC-MS/MS method, the mass spectra of propionyl coenzyme-A and methyl malonyl coenzyme-A precursor ions, and their full scan product ions were determined. MRM was used for the quantification of the analytes. The method showed good linearity and selectivity for further bioanalytical study. Conclusion: The developed UPLC-MS/MS method is capable of rapidly quantifying PCC's enzymatic activity and demonstrated suitability for assaying PCC's activity in complex biological samples. Thus, the method will be useful in validating recombinant expression of PCC, and potentially for routine quantification of mitochondrial PCC's activity level in patient cells.

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Section: Research Article | Damavandi Chan Kraus Ho and Kangmentioning

confidence: 70%

Development of an UPLC–MS/MS Method for Assaying The Enzymatic Activity of Propionyl Coenzyme-A Carboxylase

et al. 2014

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“…The mobile phase consisted of solvent A (0.5% formic acid aqueous solution, v/v) and solvent B (acetonitrile) with a flow rate of 0.2 mL/min. The gradient elution program was optimized as follows: 0-1.00 minute (5-5% B), 1.01-1.50 minutes (5-15% B), 1.51-6.00 minutes (15-25% B), 6.01-12.00 minutes (25-65% B), 12.01-13.00 minutes (65% B), and 13.01-15.00 minutes (65-5% B) [17][18][19][20]. The sample injection volume was 10 μL.…”

Section: Uplc-q-tof-ms/ms Conditionsmentioning

confidence: 99%

Tentative identification of gefitinib metabolites in non-small-cell lung cancer patient plasma using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry

et al. 2020

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Background Gefitinib is an orally potent and selective ATP-competitive inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is commonly used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC) with sensitive EGFR mutations. Multiple adverse effects associated with gefitinib, including liver and lung injuries, severe nausea, and diarrhea, have limited its clinical application. Xenobiotic-induced bioactivation is thought to be an important reason for gefitinib toxicity, which encouraged us to clarify the metabolism of gefitinib in NSCLC patients. Materials and methods An ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry (UPLCQ-TOF-MS) method was established to tentatively identify the metabolites of gefitinib in human plasma. The extracted ion chromatogram peak intensity threshold was set at 1500 cps with minimum MS and MS/MS peak intensities of 400 and 100 cps, respectively. Results A total of 18 tentative metabolites were identified. Eight novel tentative metabolites with metabolic changes in dechlorination, defluorination, and hydrogenation on the quinazoline skeleton; removal of a partial or complete 3-chloro-4-fluoroaniline-substituted group; and sulfate

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“…Since the use of this method may leave behind many matrix components which contribute to matrix effect [18] , we attempted to overcome this problem by using minute volume of mouse serum (5 µL each time) and large volumes of acetonitrile (120 µL). Since an efficient protein precipitation (>99%) could be achieved with the use of acetonitrile greater than two volumes [19] , acetonitrile in twenty-four volumes (120/5 =24) was employed during sample preparation in our study in order to further remove serum proteins as much as possible to reduce matrix effect. This was confirmed by our results, which demonstrated insignificant matrix effect (Table 2), thereby proving the effectiveness of this method in our study.…”

Section: Extraction Protocol Optimizationmentioning

confidence: 99%

Validation of a LC-MS/MS Method for Quantitative Analysis of MELK Inhibitor OTS167 in Mouse Serum: Application to a Pharmacokinetic Study

Yong¹,

Subhash²,

Ee³

et al. 2018

Preprint

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A novel, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the evaluation of OTS167 pharmacokinetics in mouse serum. SN-38 was optimized to be selected as the internal standard. Chromatographic separation was performed on a BDS Hypersil C18 column (100 x 2.1 mm, 5 µm) using gradient elution with mobile phase solvent A as water containing 0.1% formic acid and solvent B as acetonitrile containing 0.1% formic acid. The analysis was carried out using multiple reaction monitoring (MRM) with a triple-quadrupole mass spectrometer operated in the positive electrospray ionization mode. Mass transitions of 487.2 > 348.0 and 393.2 > 349.2 were monitored for OTS167 and SN-38 respectively. The standard calibration curve demonstrated high linearity at a range of 5-1000 ng/mL, with a coefficient of determination (r2) ≥ 0.996. The accuracy for OTS167 ranged from 92.3% to 102.2% and the precision was ≤ 12.7%. Recovery was consistent at about 83% to 89%. No significant matrix effect was observed. This method was successfully applied to monitor the pharmacokinetic profiles in mice over 24 h after ingestion of 5 mg/kg of OTS167. Maximum serum concentrations (3197 ng/mL) of OTS167 was observed at 1.67 hour after OTS167 ingestion via garage at 5 mg/kg and area under the curve (AUC) was 28579 h*ng/mL, suggesting that OTS167 can be quickly absorbed after oral administration.

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Rapid determination of gefitinib and its main metabolite, O-desmethyl gefitinib in human plasma using liquid chromatography–tandem mass spectrometry

Cited by 31 publications

References 14 publications

Development of an UPLC–MS/MS Method for Assaying The Enzymatic Activity of Propionyl Coenzyme-A Carboxylase

Development of an UPLC–MS/MS Method for Assaying The Enzymatic Activity of Propionyl Coenzyme-A Carboxylase

Tentative identification of gefitinib metabolites in non-small-cell lung cancer patient plasma using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry

Validation of a LC-MS/MS Method for Quantitative Analysis of MELK Inhibitor OTS167 in Mouse Serum: Application to a Pharmacokinetic Study

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