期刊
BIOMEDICAL CHROMATOGRAPHY
卷 27, 期 1, 页码 7-16出版社
WILEY-BLACKWELL
DOI: 10.1002/bmc.2741
关键词
LC-MS; MS; human plasma; 5-fluorouracil; uracil; dihydropyrimidine dehydrogenase
类别
资金
- Swiss National Science Foundation [31-119839]
The chemotherapeutic drug 5-fluorouracil (5-FU) is widely used for treating solid tumors. Response to 5-FU treatment is variable with 1030% of patients experiencing serious toxicity partly explained by reduced activity of dihydropyrimidine dehydrogenase (DPD). DPD converts endogenous uracil (U) into 5,6-dihydrouracil (UH2), and analogously, 5-FU into 5-fluoro-5,6-dihydrouracil (5-FUH2). Combined quantification of U and UH2 with 5-FU and 5-FUH2 may provide a pre-therapeutic assessment of DPD activity and further guide drug dosing during therapy. Here, we report the development of a liquid chromatographytandem mass spectrometry assay for simultaneous quantification of U, UH2, 5-FU and 5-FUH2 in human plasma. Samples were prepared by liquidliquid extraction with 10:1 ethyl acetate-2-propanol (v/v). The evaporated samples were reconstituted in 0.1% formic acid and 10 mu L aliquots were injected into the HPLC system. Analyte separation was achieved on an Atlantis dC18 column with a mobile phase consisting of 1.0 mm ammonium acetate, 0.5 mm formic acid and 3.3% methanol. Positively ionized analytes were detected by multiple reaction monitoring. The analytical response was linear in the range 0.0110 mu m for U, 0.110 mu m for UH2, 0.175 mu m for 5-FU and 0.7575 mu m for 5-FUH2, covering the expected concentration ranges in plasma. The method was validated following the FDA guidelines and applied to clinical samples obtained from ten 5-FU-treated colorectal cancer patients. The present method merges the analysis of 5-FU pharmacokinetics and DPD activity into a single assay representing a valuable tool to improve the efficacy and safety of 5-FU-based chemotherapy. Copyright (c) 2012 John Wiley & Sons, Ltd.
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