UFLC-MS/MS测定人血浆中度洛西汀浓度及临床血药浓度
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摘要
目的建立超快速液相-串联质谱法(UFLC-MS/MS)测定人血浆中度洛西汀血药浓度,并应用该方法进行血药浓度监测。方法以格列苯脲为内标,采用蛋白沉淀前处理方法,使用Phenomenex Synergi Hydro-RP色谱柱(2.00 mm×50 mm,0.004mm),以0.1%甲酸-乙腈和0.1%甲酸-水溶液为流动相,流速0.6mL·min~(-1)进行梯度洗脱。质谱采用电喷雾离子源(ESI),以多反应监测(MRM)扫描模式,在正离子电离模式下进行测定,度洛西汀和格列苯脲的定量分析离子对分别为m/z298.197/154.200和m/z494.200/369.100。结果血浆中无干扰测定的内源性物质,线性范围为5～200 ng·mL~(-1),r=0.999 3,相对回收率为93.64%～105.3%,高、中、低日内精密度(RSD)<10.0%,日间精密度(RSD)<8.2%,提取回收率、基质效应、稳定性均通过方法学验证。42例患者度洛西汀血药浓度水平受日剂量影响,年龄对度洛西汀血药浓度影响较大,性别对其血药浓度无影响。结论该方法简单快速、准确、灵敏度高,适用于度洛西汀的临床治疗药物浓度监测。度洛西汀体内血药浓度个体差异较大,受药动学特点、生理因素(年龄)影响,因此需规律监测血药浓度,并实施个体化用药,以提高临床疗效,减少不良反应。
OBJECTIVE To establish an ultra-high performance liquid chromatography method for the determination of duloxetine in human plasma and to apply this method for therapeutic drug monitoring(TDM) of duloxetine. METHODS The LC-MS/MS was applied for determination of duloxetine plasma concentration with glibenclamide as internal standard and Phenomenex Synergi Hydro-RP(2.00 mm×50 mm, 0.004 mm) as column. The mobile phases were consisted of 0.1% formic acid in acetonitrile and 0.1% formic acid in water and were pumped at a flow rate of 0.6 mL×min~(-1). Quantitative analysis was conducted in the multiple reaction monitoring modes with product ion transitions of m/z 298.197/154.200 and m/z494.200/369.100 for duloxetine and internal standard, respectively. RESULTS Chromatograms showed no endogenous interfereing peaks in the respective blank human plasma samples. The calibration was linear in the concentration range with5-200 ng·mL~(-1)(r=0.999 3) and the relative recoveries were at 93.64%-105.3%. Inter-day and intra-day RSD were less than10.0% and 8.2%, respectively. Both the extraction recovery matrix effect and the stability were validated for duloxetine in human plasma. The plasma concentration of duloxetine levels were significantly affected by age(P<0.05), but not by genter.CONCLUSION This method is simple, rapid, specific and precise for the determination of duloxetine in human plasma and it could be widely used for TDM. The plasma concentrations of duloxetine were variability, especially significantly affected by age.Rotine TDM of duloxetine may improve the treatment response.
OBJECTIVE To establish an ultra-high performance liquid chromatography method for the determination of duloxetine in human plasma and to apply this method for therapeutic drug monitoring(TDM) of duloxetine. METHODS The LC-MS/MS was applied for determination of duloxetine plasma concentration with glibenclamide as internal standard and Phenomenex Synergi Hydro-RP(2.00 mm×50 mm, 0.004 mm) as column. The mobile phases were consisted of 0.1% formic acid in acetonitrile and 0.1% formic acid in water and were pumped at a flow rate of 0.6 mL×min~(-1). Quantitative analysis was conducted in the multiple reaction monitoring modes with product ion transitions of m/z 298.197/154.200 and m/z494.200/369.100 for duloxetine and internal standard, respectively. RESULTS Chromatograms showed no endogenous interfereing peaks in the respective blank human plasma samples. The calibration was linear in the concentration range with5-200 ng·mL~(-1)(r=0.999 3) and the relative recoveries were at 93.64%-105.3%. Inter-day and intra-day RSD were less than10.0% and 8.2%, respectively. Both the extraction recovery matrix effect and the stability were validated for duloxetine in human plasma. The plasma concentration of duloxetine levels were significantly affected by age(P<0.05), but not by genter.CONCLUSION This method is simple, rapid, specific and precise for the determination of duloxetine in human plasma and it could be widely used for TDM. The plasma concentrations of duloxetine were variability, especially significantly affected by age.Rotine TDM of duloxetine may improve the treatment response.
引文
[1]孙伟,马世发,李亚军.度洛西汀治疗抑郁症的临床效果分析[J].中外医疗,2014,(4):125-126
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[11]WALDSCHMITT C,VOGEL F,PFUHLMANN B,et al.Duloxetine serum concentrations and clinical effects.Data from a therapeutic drug monitoring(TDM)survey[J].Pharmacopsychiatry,2009,42(5):189-193
[12]HIEMKE C,BAUMANN P,BERGEMANN N,et al.AGNPconsensus guidelines for therapeutic drug monitoring in psychiatry-update 2011[J].Pharmacopsychiatry,2011,44(6):195-235.
[13]SKINNER M H,KUAN H Y,SKERJANEC A,et al.Effect of age on the pharmacokinetice of duloxetine in women[J].Br JClin Pharmacol,2003,57(1):54-60
[14]陈秀娟.新型抗抑郁药的体内系统筛查方法及药代动力学研究[C].福建中医药大学,2016.6.
[15]SENTHAMIL S P,GOWDA V K,MANDAL U,et al,Determination of duloxetine in human plasma by liquid chromatography with atmospheric pressure ionization-tandem mass spectrometry and its application to pharmacokinetic study[J].J Chromatogr B Analyt Technol Biomed Life Sci,2007,858(1/2):269-275.
[16]GAJULA R,MADDELA R,BABU RAVI V,et al.A rapid and sensitive liquid chromatography-tandem mass spectrometric assay forduloxetine in human plasma:Its pharmacokinetic application[J].J Pharm Anal,2013,3(1):36-44.
[17]LOBO E D,QUINLAN T,O’BRIEN L,et al,Population pharmacokinetics of orally administered duloxetine in patients:implications for dosing recommendation[J].Clin Pharmacokinet,2009,48(3):189-197.
[18]DENG M,LI J L,ZHANG Z Q,et al.Effects of sex difference on pharmacokinetics of antidepressants[J].Chin J New Drugs Clin Rem(中国新药与临床杂志),2015,31(5):231-238.
[2]吴艳茹,肖泽萍.青少年抑郁发病的社会心理因素[J].中国行为医学科学,2007,16(3):285-286
[3]李跃华,张兰凤.抑郁症研究现状及未来研究目标探讨[J].中国医药信息杂志,2006,13(10):1-3
[4]李莉霞.度洛西汀基础与临床研究进展[J].医学导报,2009,28(2):198-199
[5]徐静,于相芬.度洛西汀的临床应用进展[J].西南军医,2011,13(4):695-697
[6]CHEN C,XU W P,HUANG Y,et al.Efficacy and Safety of Duloxetine versus Paroxetine for Adults'Depression:AMeta-Analysis[J].Chin J Evid-Based Med(中国循证医学杂志),2012,12(3):320-325
[7]岑利平,邹军辉,马云芳.度洛西汀与帕罗西汀治疗首发抑郁症疗效的对照研究[J].现代实用医学,2012,24(6):683-684.
[8]LOBO E D,BERGSTROM R F,REDDY S,et al.In vitro and in vivo ealuations of cytochrome P4501A2 interactions with duloxetine[J].Clin Pharmacokient,2008,47(3):191-202
[9]LIU D B,LI S Y,CUI H,et al.Correlation between polymorphism of cytochrome P450 1A2 gene and antidepressant clinical efficacy of duloxetine[J].Chin J Behav Med Brain Sci(中国行为医学与脑科学杂志),2012,21(5):424-426.
[10]李文标.治疗药物监测在精神科的应用及发展方向[R].首都医科大学附属北京安定医院,2012,8,25
[11]WALDSCHMITT C,VOGEL F,PFUHLMANN B,et al.Duloxetine serum concentrations and clinical effects.Data from a therapeutic drug monitoring(TDM)survey[J].Pharmacopsychiatry,2009,42(5):189-193
[12]HIEMKE C,BAUMANN P,BERGEMANN N,et al.AGNPconsensus guidelines for therapeutic drug monitoring in psychiatry-update 2011[J].Pharmacopsychiatry,2011,44(6):195-235.
[13]SKINNER M H,KUAN H Y,SKERJANEC A,et al.Effect of age on the pharmacokinetice of duloxetine in women[J].Br JClin Pharmacol,2003,57(1):54-60
[14]陈秀娟.新型抗抑郁药的体内系统筛查方法及药代动力学研究[C].福建中医药大学,2016.6.
[15]SENTHAMIL S P,GOWDA V K,MANDAL U,et al,Determination of duloxetine in human plasma by liquid chromatography with atmospheric pressure ionization-tandem mass spectrometry and its application to pharmacokinetic study[J].J Chromatogr B Analyt Technol Biomed Life Sci,2007,858(1/2):269-275.
[16]GAJULA R,MADDELA R,BABU RAVI V,et al.A rapid and sensitive liquid chromatography-tandem mass spectrometric assay forduloxetine in human plasma:Its pharmacokinetic application[J].J Pharm Anal,2013,3(1):36-44.
[17]LOBO E D,QUINLAN T,O’BRIEN L,et al,Population pharmacokinetics of orally administered duloxetine in patients:implications for dosing recommendation[J].Clin Pharmacokinet,2009,48(3):189-197.
[18]DENG M,LI J L,ZHANG Z Q,et al.Effects of sex difference on pharmacokinetics of antidepressants[J].Chin J New Drugs Clin Rem(中国新药与临床杂志),2015,31(5):231-238.