The School of Medicine, Nankai University, Tianjin 300071, China; Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050051, China.
School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei Province 050017, China.
J Pharm Biomed Anal. 2024 Nov 15;250:116405. doi: 10.1016/j.jpba.2024.116405. Epub 2024 Aug 8.
Therapeutic drug monitoring (TDM) of imatinib (IM) in cancer therapy offers the potential to improve treatment efficacy while minimizing toxicity. There was a significant correlation between unbound concentration and clinical response and toxicity, compared with total plasma concentrations, and the quantification of unbound IM and its metabolite, N-desmethyl imatinib (NDI) are of interest for TDM. However, traditional unbound drug separation methods have shortcomings, especially are susceptible to non-specific binding (NSB) of drugs to the polymer-constructed components of filter membranes, which are difficult to avoid at present. Hence it is necessary to developed a reliable separation method for the analysis of the unbound fraction of IM and NDI in TDM. We developed and validated an hollow fiber solid phase microextraction (HF-SPME) method coupled with high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) that to measure unbound IM and NDI concentration in human plasma. It used the NSB phenomenon and solve the NSB problem. The preparation procedure only involves a common vortex and ultrasonication without dilution of samples and modification of membrane. A total of 50 chronic myeloid leukemia (CML) patients were enrolled in our study. The relationship between the unbound and total concentrations for IM and NDI, as well as the concentration ratios of NDI to IM in 50 clinical plasma samples were investigated. The extraction recovery is high to 95.5-106 % with validation parameters for the methodological results were all excellent. There were both a poor linear relationship between the unbound and total concentrations for IM (r=0.504) and NDI (r=0.201) in 50 clinical plasma samples. The unbound concentration ratios of NDI to IM varied widely in CML patients. The determination of unbound IM and NDI concentration is meaningful and necessary. The developed HF-SPME method is simple, accurate and precise that could be used to measure unbound IM and NDI concentration in clinical TDM.
治疗药物监测（TDM）伊马替尼（IM）在癌症治疗中提供了提高治疗效果同时最小化毒性的潜力。与总血浆浓度相比，游离浓度与临床反应和毒性之间存在显著相关性，因此，游离 IM 及其代谢物 N-去甲基伊马替尼（NDI）的定量对于 TDM 很有意义。然而，传统的游离药物分离方法存在缺点，特别是药物对聚合物构建的过滤膜组件的非特异性结合（NSB），目前难以避免。因此，有必要开发一种可靠的分离方法来分析 TDM 中 IM 和 NDI 的游离分数。我们开发并验证了一种中空纤维固相微萃取（HF-SPME）方法，该方法与高效液相色谱串联质谱（HPLC-MS/MS）联用，用于测量人血浆中游离 IM 和 NDI 的浓度。它利用 NSB 现象并解决了 NSB 问题。制备程序仅涉及常见的涡旋和超声处理，而无需稀释样品和修饰膜。共有 50 名慢性髓性白血病（CML）患者参与了我们的研究。研究了 IM 和 NDI 的游离浓度与总浓度之间的关系，以及 50 例临床血浆样本中 NDI 与 IM 的浓度比。提取回收率高达 95.5-106%，方法学结果的验证参数均非常优秀。在 50 例临床血浆样本中，IM（r=0.504）和 NDI（r=0.201）的游离浓度之间均存在较差的线性关系。CML 患者中 NDI 与 IM 的游离浓度比差异很大。测定游离 IM 和 NDI 的浓度具有重要意义。开发的 HF-SPME 方法简单、准确、精确，可用于临床 TDM 中游离 IM 和 NDI 浓度的测定。
