Molecular Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
J Pharm Biomed Anal. 2013 Jul-Aug;81-82:89-98. doi: 10.1016/j.jpba.2013.03.025. Epub 2013 Apr 9.
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 to 5000 ng/mL for all six analytes and proved to be accurate (92.0-104.4%) and precise (CV <13.7%), 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/m(2). 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.
组蛋白去乙酰化酶抑制剂 belinostat 正在被临床评估为一种单一药物，用于治疗外周 T 细胞淋巴瘤，并与其他抗癌药物联合用于治疗多种人类癌症，包括急性白血病和实体瘤。为了确定 belinostat 在 NCI ODWG 肝功能障碍研究中的药代动力学，我们开发并验证了一种 LC-MS/MS 测定法，用于定量测定 belinostat 和五种主要代谢物在 0.05 mL 人血浆中的含量。经过蛋白质沉淀后，采用 Waters Acquity BEH C18 柱和乙腈与水的 0.1%甲酸线性梯度进行色谱分离。采用 ABI 4000Q 质谱仪，以电喷雾正离子和负离子模式进行检测。该测定法对所有六种分析物的线性范围为 30 至 5000ng/mL，且证明具有准确性（92.0-104.4%）和精密度（CV<13.7%），并符合 FDA 对生物分析方法验证的标准。我们证明了该测定法在测量接受 belinostat IV 400mg/m2 剂量给药的患者血浆中母体药物和五种主要代谢物的适用性。已经开发的 LC-MS/MS 测定法将是进一步定义 belinostat 在持续的肝功能障碍以及其他与其他抗癌药物联合研究中代谢和药理学的重要工具。
