Silver nanoparticles-tragacanth gel as a green membrane for effective extraction and determination of capecitabine.

A novel eco-friendly and effective electromembrane extraction method combining high-performance liquid chromatography with UV detection was developed for the enrichment and determination of capecitabine. Tragacanth-silver nanoparticles conjugated gel was prepared by dissolving the tragacanth powder in synthesized silver nanoparticles solution and was used as a green membrane in electromembrane extraction. The porosity and presence of silver nanoparticles in the gel were characterized by field emission scanning electron microscopy. This new electromembrane extraction approach uses neither organic solvent nor carrier agents to extract the target analyte. The best electromembrane extraction efficiency was obtained by using 4.0 mm membrane gel thickness containing 2.5% w/v of tragacanth gum, donor phase pH = 5.0, acceptor phase pH = 3.0, applied voltage 50 V, extraction time 20 min, and agitation rate 500 rpm. During method validation under the optimized conditions, good linearity dynamic range between 1 and 500 ng/mL with the coefficient of determination (R2 ) = 0.998 was obtained. Limit of detection and Limit of quantitation were estimated to be 0.84 and 1.0 ng/mL, respectively. Finally, the applicability of this method in real samples was confirmed by an acceptable performance in extraction and determination of capecitabine in human plasma samples.

Stopped-flow chemiluminescence determination of the anticancer drug capecitabine: Application in pharmaceutical analysis and drug-delivery systems.

Capecitabine is a chemotherapeutic agent used for the treatment of patients with metastatic cancers. This study aimed at determining the drug capecitabine in a simple chemiluminescence (CL) system of acidic potassium permanganate using the stopped-flow injection technique. Statistical methods were used to detect optimum conditions. The method showed two linear calibration ranges from 6.7 × 10-6 to 6.7 × 10-5 mol L-1 and from 6.7 × 10-5 to 2.7 × 10-3 mol L-1 with a detection limit of 1.5 × 10-6 mol L-1 . Chitosan-modified magnetic nanoparticles were studied in the drug-delivery experiments. According to the pH sensitivity of chitosan and low pH values in tumour cells, the chitosan-coated magnetic nanoparticles could provide a good targeting drug-delivery system to tumour sites. To evaluate the applicability of the method, the capecitabine-loaded magnetic chitosan nanoparticles were synthesized with two different cross-linkers; loading and releasing rates of the drug were investigated using the proposed CL method and an ultraviolet-visible light spectrophotometric method (absorption at 305 nm). The results showed a good correlation between the two methods, and it was found that the synthesized chitosan-modified magnetic nanoparticles could be used for pH-dependent release of capecitabine in cancer cells. Moreover, determination of capecitabine in tablets and synthetic samples was performed.

A review of the bioanalytical methods for the quantitative determination of capecitabine and its metabolites in biological matrices.

The bioanalysis of the oral anticancer drug capecitabine and its metabolites has been investigated extensively over the past years. This paper reviews methods for the bioanalysis of capecitabine and its metabolites. The focus of this review will be on sample pre-treatment, chromatography and detection. Furthermore, the choice of standards and analytical problems encountered during analysis of capecitabine and its metabolites in biological matrices will be discussed. The major challenges in the bioanalysis of capecitabine and its metabolites are the simultaneous extraction and analysis due to the differences in polarity of the analytes. Furthermore we evaluate currently described methods for the quantification of capecitabine and its metabolites. Future wishes and perspectives are stated that could serve as an inspiration for further development of assays for the quantification of capecitabine and its metabolites.

Development and validation of a sensitive method for alkyl sulfonate genotoxic impurities determination in drug substances using gas chromatography coupled to triple quadrupole mass spectrometry.

Alkyl sulfonate esters have been widely concerned as genotoxic impurities (GTIs). A gas chromatography triple-quadrupole mass spectrometry (GC-MS/MS) method has been developed for trace determination of 9 commonly encountered sulfonate esters in drug substances. Three different solvents of acetonitrile (ACN), dichloromethane (DCM) and ethyl acetate (EtOAc) were evaluated as diluents to accommodate different solubilities of test articles and multiple reactions monitoring (MRM) mode was applied for quantitation of these 9 GTIs. The method was validated in terms of linearity, sensitivity, injection precision, accuracy and solution stability. The limit of quantitation (LOQ) for the 9 commonly encountered sulfonate esters in drug substances was within 0.10-1.05 ng mL-1, which was much lower than the reported LOQs in other methods (2.5-1500 ng mL-1). It is indicated that the method gave extremely high sensitivity for all the target analytes. The correlation coefficient (r) values of 9 GTIs were no less than 0.9993 in the range of 2.0-100 ng mL-1. Recoveries of all the target analytes at 10, 20, 50 ng mL-1 (equivalent to 2, 4, 10 ppm relative to 5 mg mL-1 API samples) in two different drug substance (capecitabine and imatinib methanesulfonate) were within 75%˜120%. All alkyl sulfonates were stable in these three solvents up to 36 h. This method has been successfully used for determination of these alkyl sulfonates in capecitabine and imatinib methanesulfonate and can be further applied to other drug substances.

Identification of the Novel Capecitabine Metabolites in Capecitabine-Treated Patients with Hand-Foot Syndrome.

Hand-foot syndrome (HFS), the most common side effect of capecitabine, is a dose-limiting cutaneous toxicity with only rare therapeutic options. The causative mechanisms of HFS are still unclear. Many studies suggested that capecitabine or its metabolites caused the toxicity. This study is attempting to determine if there are any new metabolites that may be present and be linked to toxicity. For this purpose, 25 patients who ingested capecitabine orally were enrolled and divided into HFS positive and negative groups. Urine and plasma samples were collected before administration and five cycles after administration. Eleven phase I and phase II metabolites of capecitabine were detected and identified by ultraperformance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry with a metabolomic approach and MetaboLynxXS. Nine novel metabolites of capecitabine were identified herein, which were not observed in the HFS negative group. Their structures were confirmed by chemical synthesis and nuclear magnetic resonance spectroscopy. The cytotoxities of capecitabine and its metabolites on HaCaT cells were measured. Among them, M9/10 exhibited significant inhibitory activity, and they were produced via acetylation mainly by N-acetyltransferase 2. Our study comprehensively described the metabolism of capecitabine in patients with HFS and detected the novel pathways of capecitabine, which was a positive significance for the mechanism of HFS.

Comparative analysis of the interaction of capecitabine and gefitinib with human serum albumin using (19)F nuclear magnetic resonance-based approach.

Monitoring the interaction between drugs and proteins is critical to understanding drug transport and metabolism underlying pharmacodynamics. The binding capacities to human serum albumin of two anticancer drugs, capecitabine and gefitinib, were compared via an approach combining (19)F NMR, (1)H saturation transfer difference (STD) NMR, circular dichroism and docking simulations. Results showed that the two drugs interaction with human serum albumin caused (19)F NMR signal shifted to different directions. Capecitabine had accurate binding site and higher binding affinity than gefitinib. This study provided fresh insights into ligand-protein interaction and the strength of (19)F NMR approach in biomedical research was well illustrated in this case.

An in vitro liver model on microfluidic device for analysis of capecitabine metabolite using mass spectrometer as detector.

In this work, an in vitro liver model in a microfluidic device to imitate and detect prodrug metabolism was developed. A widely used prodrug capecitabine (CAP), which needs to be metabolized into active intermediate in the liver and then transformed into final effective drug in tumor cells, was selected as a model compound. The microfluidic device we exploited consists of a cell co-culture section, in which HepG2 cells were cultured to represent liver while MCF-7 cells were used to represent the tumor tissue, and an on-line solid phase extraction (SPE) section connecting to the ionization source of the ESI-Q-TOF mass spectrometer. The prodrug metabolism was realized and confirmed within this in vitro liver model as the intermediate product of the prodrug 5'-deoxy-5-fluorouridine (DFUR) was successfully detected with MS after the conditioning of HepG2 cells, and the anti-tumor effect of the active metabolite was observed through cell vitality assays of MCF-7 cells. The limit of detection (LOD) using on-chip SPE was at 10nM and semi-quantitative analysis could be realized. This system has been proved useful and practical, showing a potential to replace conventional drug screening methods.