A Rapid and Simultaneous Determination of Capecitabine and Its Activated Metabolites in Human Plasma by LC-MS/MS
Luqi XIONG1(),Boxin ZHAO2()
1.Department of Pharmacy, the Central Hospital of Huizhou City, Guangdong Province, Huizhou 516001,China 2.Department of Pharmacy, Southern Hospital of Southern Medical University, Guangzhou 510515,China
Objective To develop a simple and rapid method for simultaneous quantification of capecitabine and its active metabolite(5-fluorouracil )in human plasma by liquid chromatography—tandem mass spectrometry (LC-MS/MS) and apply it to clinical practice. Methods After a protein precipitation using acetonitrile, the supernatant taken from the centrifugal plasma samples was analyzed directly. With a mobile phase comprising acetonitrile/0.1% aqueous formicacid and 25 mmol·L-1ammonium acetate (95:5) and an electrospray ion (ESI) source, samples contained capecitabine and 5-fluorouracil were quantitative analyzed. The MS/MS detection was performed using multiple reaction monitoring (MRM), in positive mode. The mass transitions of the protonated precursor/product ion pairs were used to record the selected ion mass chromatograms of capecitabine and 5-fluorouracil were m/z 358.1→154.1 and m/z 129→42.1, respectively. 20 patients were receiving chemotherapy with capecitabine were then the steady state trough concentration of capecitabine and 5-fluorouracil in the patients’ plasma were monitored. The clinical application of the detection method was evaluated through the correlation of single point concentration of capecitabine and 5-fluorouracil. Results The linear calibration curve was obtained in the concentration range from 39.062 5-10 000 ng·mL-1(R2=0.999)for both capecitabine and 5-fluorouracil with the limit of quantification was 39.062 5 ng·mL-1. The extraction recoveries of capecitabine at three concentration levels(78.125,625 and 5000 ng·mL-1) and that of the 5-fluorouracil were (78.22±3.15)%,(75.37±2.99)%,(81.05±2.78)% and (70.45±2.19)%,(72.56±1.68)%,(72.02±1.72)%,respectively. The intra-and inter-run precisions,expressed as the relative standard deviation(RSD)were less than 5% for both of capecitabine and 5-fluorouracil. The detection result acquired from the plasma samples indicated that there was differences for the plasma concentration of capecitabine and 5-fluorouracil between individuals and that there was a poor correlation of plasma concentration between the capecitabine and its active metabolite. Conclusion The method is sensitive,specific and validate rapid for simultaneous quantification of capecitabine and 5-fluorouracil in human plasma by liquid chromatography—tandem mass spectrometry and will be successfully applied for clinical practice to improve the effectiveness and security of chemotherapy regimens with capecitabine.
熊璐琪,赵博欣. 液相色谱-串联质谱法快速同时测定人血浆中卡培他滨及其活性代谢物[J]. 医药导报, 2019, 38(6): 786-791.
Luqi XIONG,Boxin ZHAO. A Rapid and Simultaneous Determination of Capecitabine and Its Activated Metabolites in Human Plasma by LC-MS/MS. Herald of Medicine, 2019, 38(6): 786-791.
TOWNSEND D M,TEW K D.The role of glutathione-S-transferase in antrcancer® drug resistance[J].Oncogene,2003,22:7369-7375.
DAHL O,FLUGE O,CARLSEN E,et al.Final results of a randomized phase Ⅲ study on adjuvant chemotherapy with 5-FU and levamisol in colon and rectum cancer stage Ⅱand Ⅲ by the Norwegian Gastrointestinal Cancer Group[J].Acta Oncol,2009,48(3):368-376.
ZACHARIAE R,PAULSEN K,MEHLSEN M,et al.Chemot herapy-in-duced nausea,vomiting,and fatigue-the role of individual differences related to sensory perception and autonomic reactivity[J].Psychother Psychosom,2007,76(6):376-384.
GAMELIN E,DELVA R,JACOB J,et al.Individual fluorou-racil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage:results of a multicenter randomized trial of patients with metastatic colorectal cancer[J].J Clin Oncol,2008,26(13):2099-2105.
DHANANJEYAN M R,LIU J,BYKOWSKI C,et al.Rapid and simultaneous determination of capecitabine and its metabolites in mouse plasma,mouse serum,and in rabbit bile by high-performance liquid chromatography[J].J Chromatography A,2007,1138(1/2):101-108.
YUKO T,YUKIO K,MASAKO U,et al.Pharmacokinetic analysis of capecitabine,a triple prodrug of 5-FU in humans:the mechanism for tumor selective accumulation of 5-FU[J].Pharm Res,2001,18(8):1190-1201.
SALVADOR A,MILLERIOUX L,RENOU A.Simultaneous LC-MS-MS analysis of capecitabine and its metabolites after off-line SPE from human plasma[J].Chromatographia,2006,63:609-615.
HERMES L P,SHERRY W,CHEESTER B.Development of a sensitive and selective LC-MS/MS method for the determination of α-fluoro-β-alanine,5-fluorouracil and capecitabine in human plasma[J].J Chromatogr B,2009,877:1040-1046.
MONTANGE D,BDRARD M,DEMARCHI M,et al.An APCI LC-MS/MS method for routine determination of capecitabine and its metabolites in human plasma[J].J Mass Spectrom,2010,45(6):670-677.
TSUME Y,PROVODA C J,AMIDON G L.The achievement of mass balance by simultaneous quantification of floxuridine prodrug,floxuridine,5-fluorouracil,5-dihydrouracil,α-fluoro-β-ureidopropionate,α-fluoro-β-alanine using LC-MS[J].J Chromatogr B,2011,879(13/14):915-920.