Boddy Alan V, Sludden Julieann, Griffin Melanie J, Garner Colin, Kendrick John, Mistry Pritesh, Dutreix Catherine, Newell David R, O'Brien Stephen G
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
Clin Cancer Res. 2007 Jul 15;13(14):4164-9. doi: 10.1158/1078-0432.CCR-06-2179.
To investigate the potential use of accelerator mass spectrometry (AMS) in the study of the clinical pharmacology of imatinib.
Six patients who were receiving imatinib (400 mg/d) as part of their ongoing treatment for chronic myeloid leukemia (CML) received a dose containing a trace quantity (13.6 kBq) of (14)C-imatinib. Blood samples were collected from patients before and at various times up to 72 h after administration of the test dose and were processed to provide samples of plasma and peripheral blood lymphocytes (PBL). Samples were analyzed by AMS, with chromatographic separation of parent compound from metabolites. In addition, plasma samples were analyzed by liquid chromatography/mass spectrometry (LCMS).
Analysis of the AMS data indicated that imatinib was rapidly absorbed and could be detected in plasma up to 72 h after administration. Imatinib was also detectable in PBL at 24 h after administration of the (14)C-labeled dose. Comparison of plasma concentrations determined by AMS with those derived by LCMS analysis gave similar average estimates of area under plasma concentration time curve (26 +/- 3 versus 27 +/- 11 microg/mL.h), but with some variation within each individual.
Using this technique, data were obtained in a small number of patients on the pharmacokinetics of a single dose of imatinib in the context of chronic dosing, which could shed light on possible pharmacologic causes of resistance to imatinib in CML.
研究加速器质谱法（AMS）在伊马替尼临床药理学研究中的潜在应用。
6例正在接受伊马替尼（400mg/d）治疗慢性髓性白血病（CML）的患者接受了一剂含有微量（13.6 kBq）的（14）C - 伊马替尼。在给予试验剂量前及给药后长达72小时的不同时间点采集患者血样，并进行处理以获得血浆和外周血淋巴细胞（PBL）样本。通过AMS分析样本，同时采用色谱法将母体化合物与代谢产物分离。此外，血浆样本通过液相色谱/质谱联用（LCMS）进行分析。
对AMS数据的分析表明，伊马替尼吸收迅速，给药后72小时内血浆中均可检测到。给予（14）C标记剂量后24小时，PBL中也可检测到伊马替尼。将AMS测定的血浆浓度与LCMS分析得出的浓度进行比较，血浆浓度 - 时间曲线下面积的平均估计值相似（26±3与27±11μg/mL·h），但个体间存在一定差异。
采用该技术，在少数患者中获得了单剂量伊马替尼在长期给药背景下的药代动力学数据，这可能有助于揭示CML中对伊马替尼耐药的潜在药理学原因。
