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. 2019 Jan 3:2019:9371790.
doi: 10.1155/2019/9371790. eCollection 2019.

A Sensitive and Efficient Method for Determination of Capecitabine and Its Five Metabolites in Human Plasma Based on One-Step Liquid-Liquid Extraction

Zhipeng Wang #  1 , Xinxing Li #  2 , Yang Yang  1 , Feng Zhang  1 , Mingming Li  1 , Wei Chen  1 , Shouhong Gao  1 , Wansheng Chen  1
Affiliations

A Sensitive and Efficient Method for Determination of Capecitabine and Its Five Metabolites in Human Plasma Based on One-Step Liquid-Liquid Extraction

Zhipeng Wang et al. J Anal Methods Chem. .

Abstract

Colorectal cancer is the most common critical disease both in the developed and developing countries. Capecitabine, which has served in clinical practice at least for 10 years, is a first-line antidigestive tract cancer drug for its better efficacy, patient compliance, and lower side effects. An ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method has been developed and completely validated for simultaneous determination of capecitabine and its five metabolites in human plasma from colorectal cancer patients after administration of capecitabine tablet. One-step liquid-liquid extraction was successfully applied using ethyl acetate and isopropanol (19 : 1, V : V) for sample pretreatment. Chromatographic separation was achieved within 5 min based on an Atlantis T3-C18 column (3.0 µm, 2.1 × 100 mm) with gradient elution using mobile phases consisting of 0.0075% formic acid in water (pH 4) and in acetonitrile, and the flow rate was 0.3 mL/min. Linear range was approximately 20.0-5000.0 ng/mL for all analytes. Linear correlation coefficients were >0.99 for all regression curves. The intraday and interday accuracy and precision of the method were within ±15.0% and less than 15.0%, respectively. The mean recovery and matrix effect as well as stability of all the analytes ranged from 59.27% to 90.15% and from 74.84% to 114.48% as well as within ±15.0%. This simple, rapid, and sensitive method was successfully applied in 42 sparse clinical samples to verify its practicability.

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Figures

Figure 1
Figure 1
The metabolic pathways and targets of Cap. Cap: capecitabine; 5'-DFCR: 5'-deoxy-5-fluorocytidine; 5'-DFUR: doxifluridine; 2'-DFUR: 5-fluoro-2'-deoxyuridine; 5-FU: 5-fluorouracil; FUH2: dihydrofluorouracil; FBAL: α-fluoro-β-alanine; CES: carboxylesterase; CDA: cytidine deaminase; TP: thymidylate phosphorylase; TS: thymidylate synthetase; FUMP: fluorouridine monophosphate; FUTP: fluorouridine triphosphate; FdUTP: deoxyfluorouridine triphosphate; FdUMP: deoxyfluorouridine monophosphate.
Figure 2
Figure 2
Product ions chromatograms and fragment structures of Cap and its five metabolites. (a) Cap; (b) 5'-DFCR; (c) 5'-DFUR; (d) 2'-DFUR; (e) 5-FU; (f) FUH2.
Figure 3
Figure 3
Representative MRM chromatograms of Cap and its five metabolites. (a) Blank sample; (b) blank sample spiked IS; (c) blank sample spiked with LLOQ concentration of Cap and its metabolites; (d) real sample collected from one colorectal cancer patient after administration of Cap.
Figure 4
Figure 4
Comparative chromatograms of carryover of Cap and its five metabolites. (a) Highest calibration standard sample and (b) blank sample.
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