A sensitive and specific liquid chromatography–tandem mass spectrometric method for determination of belinostat in plasma from liver cancer patients

Wang, Ling Zhi; Chan, David; Park, Yeon Hee; Wan, Seow Ching; Chan, Stephen L.; Chan, Anthony Tak-cheung; Lee, Soo‐Chin; Lee, How Sung; Goh, Boon Cher

doi:10.1016/j.jchromb.2010.07.015

Cited by 10 publications

(11 citation statements)

References 11 publications

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“…Collected blood samples were centrifuged at 3000 g for 10–15 min and the plasma (supernatant) was separated from the cell pellet and stored in plain tubes at –80°C till analysis. The concentrations of belinostat and belinostat glucuronide were quantified by a modified high-performance liquid chromatography/mass spectrometry method [24]. Briefly, vorinostat-G was used as the internal standard for belinostat-G.…”

Section: Methodsmentioning

confidence: 99%

Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

et al. 2013

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Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.Trial RegistrationClinicalTrials.gov NCT00321594

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Section: Methodsmentioning

confidence: 99%

Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

et al. 2013

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“…Several LC–MS/MS methods have been reported for the quantification of HDAC inhibitors in various matrices such as plasma, serum, urine, PBMCs and tissue homogenate. Most of the reported methods are used in clinical applications (Chan et al ; Li & Chan, ; Hwang et al ., ; Du et al ., ; Parise et al ; Chen et al ; Patel et al ., ; Wang et al ., ; Kiesel et al ., ; Liu et al ., ; Gu et al ., ) compared with preclinical applications (Chan et al ., ; Li & Chan, ; Yeo et al ., ; Chen et al ., ; Estella‐Hermoso de Mendoza., ; Mohamed et al ., ; Wang, Chen, Wen, Zhang, & Ma, ; Wu, Chen, Wen, Zhang, & Lin, ). All of the LC–MS/MS methods have employed ESI positive mode for quantitation (Table ).…”

Section: Discussionmentioning

confidence: 98%

“…The salient feature of this method was to reduce the interference if any from the belinostat glucuronide and, therefore, precautions were taken: (a) ensuring that a low extraction recovery for belinostat glucuronide with a relatively higher extraction was achieved for the belinostat; and (b) selection of chromatographic column and choice of mobile phase/flow rate such that adequate separation of ~2 min was achieved between the belinostat peak and the glucuronide metabolite peak. In order to improve sensitivity in the mass spectral analysis, a positive ion mode was employed with the addition of 0.1% formic acid in the mobile phase to improve the ionization of both analytes (Wang et al ., ).…”

Section: Scopementioning

confidence: 97%

Review of bioanalytical assays for the quantitation of various HDAC inhibitors such as vorinostat, belinostat, panobinostat, romidepsin and chidamine

Suresh

Devaraj

Srinivas³

et al. 2016

Biomedical Chromatography

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Histone deacetylase inhibitors (HDAC inhibitors) are used to treat malignancies such as cutaneous T cell lymphoma and peripheral T cell lymphoma. Only four drugs are approved by the US Food and Drug Administration, namely vorinostat, romidepsin, panobinostat and belinostat, while chidamide has been approved in China. There are a number of bioanalytical methods reported for the measurement of HDAC inhibitors in clinical (human plasma and serum) and preclinical (mouse plasma, rat plasma, urine and tissue homogenates, etc.) studies. This review covers various HDAC inhibitors such as vorinostat, romidepsin, panobinostat, belinostat and chidamide. In addition to providing a comprehensive review of the available methods for the above mentioned HDAC inhibitors, it also provides case studies with perspectives for chosen drugs. Based on the review, it is concluded that the published methodologies using either HPLC or LC-MS/MS are well suited for the quantification of HDAC inhibitors in various biological fluids to delineate pharmacokinetic data.

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“…A previously reported assay for the quantitation of belinostat alone was validated over the range of 0.5–1000 ng/mL with a run time of 6 min, which could detect but not quantitate the glucuronide metabolite[8]. Employing UPLC chromatography allowed us to quantitate belinostat and 5 metabolites in a similar time-span, across a higher concentration range of 30–5000 ng/mL, which was adequate to evaluate the pharmacokinetic profiles of all analytes in a patient.…”

Section: Discussionmentioning

confidence: 99%

LC–MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma

Kiesel

Parise

Tjørnelund³

et al. 2013

Journal of Pharmaceutical and Biomedical Analysis

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The histone deacetylase inhibitor belinostat is being evaluated clinically as a single agent in the treatment of Peripheral T-cell lymphomas and in combination with other anticancer agents to treat a wide range of human cancers including acute leukemias and solid tumors. To determine the pharmacokinetics of belinostat in the NCI ODWG liver dysfunction study, we developed and validated an LC-MS/MS assay for the quantitation of belinostat and five major metabolites in 0.05 mL human plasma. After protein precipitation, chromatographic separation was achieved with a Waters Acquity BEH C18 column and a linear gradient of 0.1% formic acid in acetonitrile and water. Detection with an ABI 4000Q mass spectrometer utilized both electrospray positive and negative mode ionization. The assay was linear from 30–5000 ng/mL for all six analytes and proved to be accurate (92.0–104.4%) and precise (<13.7%CV), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring parent drug and five major metabolites in plasma from a patient who was administered belinostat IV at a dose of 400 mg/m2. The LC-MS/MS assay that has been developed will be an essential tool to further define the metabolism and pharmacology of belinostat in the ongoing liver organ dysfunction as well as other studies that investigate belinostat with other anticancer agents.

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A sensitive and specific liquid chromatography–tandem mass spectrometric method for determination of belinostat in plasma from liver cancer patients

Cited by 10 publications

References 11 publications

Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

Review of bioanalytical assays for the quantitation of various HDAC inhibitors such as vorinostat, belinostat, panobinostat, romidepsin and chidamine

LC–MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma

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