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,Feng Zhang,Shouhong Gao,Wei Chen,Yang Yang,Wansheng Chen,Mingming Li,Xinxing Li

doi:10.1155/2019/9371790

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.

Highlights

Colorectal cancer is the leading cause of death in both developed countries and developing countries, and heavy social and economic burden have been brought by this malignant disease
In China, there were 310,244 new colorectal cancer cases, which ranked fourth in all new cancer cases (9.20%), and the people who died of colorectal cancer was
Cap was metabolized by carboxylesterase to 5’-deoxy-5-fluorocytidine (5’-DFCR), and cytidine deaminase transforms the 5’-DFCR to doxifluridine (5’-DFUR), and this step could be detected in other normal or tumor tissues. 5’-DFUR would be preferably metabolized to 5-FU in tumor tissue by activityenhanced thymidine phosphorylase with more than 10 times higher concentration of product compared with other normal tissue [4]. is partial targeted drug delivery was believed to improve the treatment efficacy and tolerance of Cap

Summary

Introduction

Colorectal cancer is the leading cause of death in both developed countries and developing countries, and heavy social and economic burden have been brought by this malignant disease. According to the GLOBOCAN2012, colorectal cancer ranked third in new cancer cases worldwide, and second in the developed countries, with estimated 1.4 million cases and 693,900 deaths occurred in 2012 worldwide [1]. As an oral administration prodrug, three metabolic steps were needed to catabolize itself to the active agent 5-FU both in liver and target cells. Is partial targeted drug delivery was believed to improve the treatment efficacy and tolerance of Cap. It had been reported that approximately 80% of 5-FU is catabolized to inactive product dihydrofluorouracil (FUH2) by the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD) in liver, and declined activity of DPD often caused a longer retention of 5-FU [5,6,7]. FUH2 would be excreted along with urine as α-fluoro-β-alanine

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Results