8种抗精神病药、13种抗抑郁药及9种活性代谢物在人血清中的稳定性研究  

Study on the stability of 8 antipsychotics,13 antidepressants and 9 active metabolites in human serum

作　　者：贺静[1,2] 凌四海[1] 何山[1] 周春燕[1] 郭桂欣[1,2] 李文标[1,2] He Jing;Ling Sihai;He Shan;Zhou Chunyan;Guo Guixin;Li Wen-biao(Department of Clinical Laboratory,Beijing Key Laboratory of Mental Disorders,National Clinical Research Center for Mental Disorders&National Center for Mental Disorders,Beijing Anding Hospital,Capital Medical University,Beijing 100088,China;Advanced Innovation Center for Human Brain Protection,Capital Medical University,Beijing 100069,China)

机构地区：[1]首都医科大学附属北京安定医院检验科,国家精神疾病医学中心,国家精神心理疾病临床医学研究中心,精神疾病诊断与治疗北京市重点实验室,北京100088 [2]首都医科大学人脑保护高精尖创新中心,北京100069

出　　处：《实用药物与临床》2024年第6期401-408,共8页Practical Pharmacy and Clinical Remedies

基　　金：首都临床特色应用研究与成果推广项目(Z171100001017075)。

摘　　要：目的研究8种抗精神病药(阿立哌唑、氨磺必利、奥氮平、喹硫平、利培酮、帕利哌酮、氯氮平、氯丙嗪)、13种抗抑郁药(阿米替林、安非他酮、度洛西汀、多虑平、氟伏沙明、氟西汀、氯米帕明、米氮平、帕罗西汀、曲唑酮、舍曲林、文拉法辛、西酞普兰)及9种活性代谢物(脱氢阿立哌唑、脱烷基喹硫平、去甲氯氮平、去甲替林、羟安非他酮、去甲多虑平、去甲氟西汀、去甲氯米帕明、O-去甲文拉法辛)在人血清中的稳定性,为这些药物在实施治疗药物监测过程中的样本传输、检测、存储条件的确定以及质控血清、标准曲线校准血清保存条件和保存期限的确定提供参考数据。方法以混合健康人血清为基质配制质控血清,进行稳定性考察,分别考察目标药物及活性代谢产物在室温(12 h、24 h、72 h)、2~8℃冷藏(2 d、5 d、7 d)、-80℃超低温(14个月)保存及3次反复冻融的稳定性。采用超高效液相色谱-串联质谱法检测被分析物的血清浓度。结果安非他酮在室温、2~8℃冷藏保存条件下质控血清测得浓度的负偏倚>40%,但在-80℃超低温保存14个月及3次反复冻融条件下测得浓度的偏倚均在±15%内。其他药物及代谢物在各考察条件下测得浓度的偏倚均在±15%内。但在室温条件下,随着放置时间延长,脱烷基喹硫平、度洛西汀、氟伏沙明、舍曲林、氟西汀、去甲氟西汀、去甲替林、阿米替林、氯丙嗪、氯米帕明及去甲氯米帕明测得浓度的负偏倚逐渐增加。结论在人血清基质中,安非他酮在室温和2~8℃冷藏的条件下不稳定。其余8种抗精神病药、12种抗抑郁药及9种活性代谢物在室温下可稳定72 h,但在室温下存放超24 h后,部分药物存在降解趋势,建议放入2~8℃的冰箱中保存,在此条件下可稳定至少7 d。本文所研究的所有药物及活性代谢物的质控血清可在-80℃冰箱中保存至少14个月,Objective To study the stability of 8 antipsychotics(aripiprazole,amisulpride,olanzapine,quetiapine,risperidone,paliperidone,clozapine,chlorpromazine),13 antidepressants(amitriptyline,bupropion,duloxetine,doxepin,fluvoxamine,fluoxetine,clomipramine,mirtazapine,paroxetine,trazodone,sertraline,venlafaxine,citalopram)and 9 active metabolites(dehydroaripiprazole,N-desalkyl quetiapine,norclozapine,nortriptyline,hydroxybupropion,N-desmethly doxepin,N-desmethyl fluoxetine,N-desmethyl clomipramine,O-desmethyl venlafaxine)in human serum,and provide reference data for the determination of the sample transportation,detection and storage conditions and the determination of storage condition and period of validity for quality control samples and calibration standards in the process of therapeutic drug monitoring.Methods The stability was investigated using quality control samples made by pooled human serum spiked with target drug or metabolites.The stability was evaluated at room temperature(12 h,24 h,72 h),2~8℃refrigeration(2 d,5 d,7 d),-80℃ultra-low temperature refrigeration(14 months)and three repeated freeze-thaw conditions.The serum concentration of these drugs was determined by UPLC-MS/MS.Results The negative bias of bupropion serum concentration was greater than 40%when its quality control samples were stored at room temperature and 2~8℃,but after 14 months'storage in-80℃refrigerator and freeze-thaw for three times,the bias of serum concentration was within±15%.The bias of other drugs'concentration and metabolites under various examination conditions was within±15%.However,at room temperature,as the storage time increased,the negative serum concentration bias of dealkylated quetiapine,duloxetine,fluvoxamine,sertraline,fluoxetine,norfluoxetine,nortriptyline,amitriptyline,chlorpromazine,clomipramine,and norclomipramine gradually increased.Conclusion The serum quality control samples of bupropion is unstable at room temperature and 2~8℃ refrigeration conditions.Except for bupropion,serum quality control sample

关 键 词：抗精神病药 抗抑郁药 稳定性 治疗药物监测 

分 类 号：R969.1[医药卫生—药理学]