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UPLC-MS/MS法同时测定人血浆中5-FU及其代谢产物5-FUH2的浓度及应用
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| 篇名： | UPLC-MS/MS法同时测定人血浆中5-FU及其代谢产物5-FUH2的浓度及应用 |
| TITLE： | Simultaneous Determination of 5-FU and Its Metabolites 5-FUH2 in Human Plasma by UPLC-MS/MS and Appli- cation |
| 摘要： | 目的：建立同时测定人血浆中5-氟尿嘧啶（5-FU）及其代谢产物5-氟-5，6-二氢尿嘧啶（5-FUH2）浓度的方法，并应用于临床。方法：血浆样品经乙酸乙酯二次萃取处理后，以5-溴尿嘧啶（5-Bru）为内标，采用超高效液相色谱-串联质谱技术（UPLC-MS/MS）测定。色谱柱为AcquityUPLCHSST3，流动相为甲醇-水（30∶70，V/V），流速为0.3mL/min，柱温为20℃，进样量为5μL。采用电喷雾离子源，以多反应监测进行负离子扫描，毛细管电压为1.5kV，锥孔电压为20V，脱溶剂温度为450℃，脱溶剂气流为850L/h，锥孔气流速为50L/h；用于定量分析的离子对分别为m/z129.00→41.90（5-FU）、m/z130.87→82.92（5-FUH2）、m/z189.00→42.10（5-Bru）。选择2020年8－10月哈尔滨医科大学附属肿瘤医院接受5-FU持续静脉滴注46h为基础化疗方案治疗的晚期结直肠癌患者10例，测定其持续静脉滴注18～30h时的5-FU稳态血药浓度及5-FUH2血药浓度，计算5-FU药-时曲线下面积（AUC）和5-FUH2/5-FU浓度比值。结果：5-FU、5-FUH2检测质量浓度的线性范围均为20～1000ng/mL（R2均大于0.990），定量下限均为20ng/mL；精密度试验的RSD均小于20％，相对误差在±10％范围内；提取回收率、基质效应均不影响待测物的测定。10例晚期结直肠癌患者中，5-FU稳态血药浓度为180.04～622.83ng/mL，AUC为8.28～28.65mg·h/L；5-FUH2血药浓度为336.48～948.43ng/mL；5-FUH2/5-FU浓度比值为0.93～4.21；10例患者的5-FUAUC存在约3～4倍的个体差异。结论：所建方法精密度、准确性均较好，灵敏度较高且操作简便，可用于晚期结直肠癌患者体内5-FU血药浓度的监测。 |
| ABSTRACT： | OBJECTIVE：To establish the method for simultaneous determination of 5-fluorouracil（5-FU）and its metabolites 5-fluoro-5，6-dihydrouracil （5-FUH2） in human plasma ，and apply it in the clinic. METHODS ：After plasma samples were processed twice by ethyl acetate ，UPLC-MS/MS method was adopted using 5-bromouracil （5-Bru） as internal standard. The determination was performed on Acquity UPLC HSS T 3 column with mobile phase consisted of methanol-water （30 ∶ 70，V/V）at the flow rate of 0.3 mL/min. The column temperature was 20 ℃，and sample size was 5 μL. An electrospray ion source was used to carry out negative ion scanning with multiple reaction monitoring. The capillary voltage was 1.5 kV；the taper hole voltage was 20 V；the desolvent temperature was 450 ℃；the desolvent air flow was 850 L/h；the cone hole gas velocity was 50 L/h. The ion transitions for quantitative analysis were m/z 129.00→41.90（5-FU），m/z 130.87→82.92（5-FUH2），m/z 189.00→42.10（5-Bru）， respectively. From Aug. to Oct. 2020，10 patients with advanced colorectal cancer were treated with continuous intravenous drip of 5-FU for 46 hours were collected from Harbin Medicinal University Cancer Hospital. Steady-state plasma concentration of 5-FU and plasma concentration of 5-FUH2 were determined at 18-30 h of continuous intravenous drip. The area under the curve （AUC）for 5-FU and concentration ratio of 5-FUH2/5-FU were calculated. RESULTS ：The linear range of 5-FU and 5-FUH2 were 20 to 1 000 μg/mL（R 2＞0.990）. The quantification limits were 20 ng/mL. RSDs of precision test were all lower than 20％，and relative error ranged ±10％. The extraction recovery and matrix effects didn ’t affect the determination of substance to be measured. Among 10 patients with advanced colorectal cancer ，the steady-state concentration of 5-FU were 180.04-622.83 ng/mL，and AUC of 5-FU ranged from 8.28 to 28.65 mg·h/L. The concentration of 5-FUH2 ranged 336.48-948.43 ng/mL，and concentration ratio of 5-FUH2/ 5-FU ranged 0.93-4.21. AUC of 5-FU in 10 patients had about 3-4 fold individual differences. CONCLUSIONS ：The established method has good precision and accuracy ，high sensitivity ，and simple operation. It can be used for plasma monitoring of 5-FU in patients with advanced colorectal cancer. |
| 期刊： | 2021年第32卷第04期 |
| 作者： | 佟志强，吴东媛，张娟，程梦飞，张硕，董梅 |
| AUTHORS： | TONG Zhiqiang ，WU Dongyuan ，ZHANG Juan，CHENG Mengfei ，ZHANG Shuo，DONG Mei |
| 关键字： | 超高效液相色谱-串联质谱法；5-氟尿嘧啶；5-氟-5，6-二氢尿嘧啶；血药浓度 |
| KEYWORDS： | UPLC-MS/MS； 5-FU； 5-FUH2； Plasma |
| 阅读数： | 388 次 |
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