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首页> 外文期刊>Therapeutic Drug Monitoring >Robust, high-throughput LC-MS/MS method for therapeutic drug monitoring of cyclosporine, tacrolimus, everolimus, and sirolimus in whole blood.
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Robust, high-throughput LC-MS/MS method for therapeutic drug monitoring of cyclosporine, tacrolimus, everolimus, and sirolimus in whole blood.

机译：用于全血中环孢素，他克莫司，依维莫司和西罗莫司治疗药物监测的稳健，高通量LC-MS / MS方法。

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The authors describe a fast, robust, and straightforward liquid chromatography and tandem mass spectrometry (LC-MS/MS) method with the use of a single LC-MS/MS system for cyclosporine A, tacrolimus, sirolimus, and everolimus in whole blood. The purpose of this method was to replace the immunoassay (IA) methods used in the laboratory of a hospital performing most organ transplantations (including heart, lung, liver, kidneys, bone marrow, and intestinal tract). Several LC-MS/MS methods have been described so far; however, most of them require complicated online extraction procedures. The described LC-MS/MS method uses a chromatographic gradient in combination with protein precipitation as sample preparation. The chromatographic method is capable of separating otherwise interfering peaks, with an analysis time of 2.6 minutes. Analyses were performed on a triple quadrupole LC-MS/MS system, with a C18 column held at 60 degrees C. Sample preparation required only 1 precipitation/dilution step. Sirolimus and everolimus are prepared and measured separately from tacrolimus and cyclosporine. During method development, it was found that the use of zinc sulfate provides process efficiency results of about 100% for tacrolimus and cyclosporine A, but only 81% and 87% for sirolimus and everolimus, respectively. With the developed sample preparation without zinc sulfate for sirolimus and everolimus, process efficiencies were 99% and 108%, respectively. The methods have been fully validated, and in a comparative study, patient samples were analyzed with IA and our developed LC-MS/MS methods. In the comparative studies, correlations (R2 values) of more than 0.85 were found between the IA and the new LC-MS/MS patient blood levels. There was a systematic deviation in blood levels measured by LC-MS/MS compared with IAs for cyclosporine A (17% lower than with immunoassay) and everolimus (30% lower than with IA). There seemed to be little or no systematic deviation for sirolimus and tacrolimus. The controls determined by the LC-MS/MS method over the past 10 months showed coefficient of variations of no more than 8.0% for each of the 4 immunosuppressants. In conclusion, the authors found the developed methods to be cost saving, more flexible, and more sensitive and that these methods have larger linear ranges than the previously used IA methods. The methods are already used for more than 20,000 patient samples in the daily routine, analyzing approximately 70 patient samples per day.
机译：作者介绍了一种使用单一LC-MS / MS系统对全血中环孢菌素A，他克莫司，西罗莫司和依维莫司进行快速，稳健和直接的液相色谱和串联质谱分析（LC-MS / MS）的方法。此方法的目的是代替执行大多数器官移植（包括心脏，肺，肝，肾，骨髓和肠道）的医院实验室中使用的免疫测定（IA）方法。到目前为止，已经描述了几种LC-MS / MS方法。但是，其中大多数都需要复杂的在线提取程序。所描述的LC-MS / MS方法使用色谱梯度结合蛋白质沉淀作为样品制备方法。色谱方法能够分离其他干扰峰，分析时间为2.6分钟。在三联四极杆LC-MS / MS系统上进行分析，C18色谱柱保持在60摄氏度。样品制备仅需1个沉淀/稀释步骤。西罗莫司和依维莫司分别与他克莫司和环孢菌素一起制备和测定。在方法开发过程中，发现使用硫酸锌可为他克莫司和环孢菌素A提供约100％的工艺效率结果，但对于西罗莫司和依维莫司分别为81％和87％。使用开发的不含硫酸锌的西罗莫司和依维莫司的样品前处理，处理效率分别为99％和108％。该方法已得到充分验证，并且在一项比较研究中，使用IA和我们开发的LC-MS / MS方法对患者样品进行了分析。在比较研究中，IA与新的LC-MS / MS患者血液水平之间的相关性（R2值）大于0.85。通过LC-MS / MS与IAs相比，环孢素A（比免疫测定低17％）和依维莫司（比IA低30％）测得的血液水平存在系统性偏差。西罗莫司和他克莫司似乎几乎没有或没有系统的偏差。在过去的10个月中，通过LC-MS / MS方法确定的对照显示出4种免疫抑制剂中每一种的变异系数均不超过8.0％。总之，作者发现开发的方法节省成本，更灵活，更灵敏，并且与以前使用的IA方法相比，这些方法具有更大的线性范围。这些方法已被每天用于超过20,000个患者样品，每天分析大约70个患者样品。

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