基于生物样品在线富集技术的临床毛细管电泳方法学研究
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摘要
临床生物样品分析是临床药物治疗的重要辅助手段，是化学、生物学与医学的桥梁。临床生物样品分析主要包括代谢组学研究，临床治疗药物监测、药代动力学研究和生化样品分析。常见的生物样品分析方法有色谱法、光谱法、微生物法和免疫法。较其他三种方法，色谱法能够结合光谱法，免疫法和生物法的优势，利用自身的分离效能，能够准确，有效地分离分析临床生物样品。主流的色谱分析法为气相色谱法、高效液相色谱法和毛细管电泳法。
近几年，毛细管电泳作为一种新型的分离分析技术，较常规色谱有分析速度快、分离效能高，分析成本低，使用分析体系较其他色谱法更接近生物体液环境的优势，而越来越被重视，成为主流的生物样品分析方法。但当使用紫外检测器时，由于毛细管电泳的进样量和检测窗小，灵敏度受到限制。为了解决这个问题，场放大技术在毛细管电泳中起到了至关重要的作用。它主要原理是分析物在两个导电性不同的相界面上电泳速度的不同而形成富集效应，从而实现较高灵敏度的快速分离分析。
本课题选择盐酸氨溴索、苯磺酸氨氯地平及米氮平为研究对象，是因为它们给药剂量小，半衰期长，血药浓度低，希望通过建立合适的在线场放大毛细管电泳法，实现灵敏、快速、低耗的分离分析，并将其用于测定盐酸氨溴索、苯磺酸氨氯地平对映体及米氮平和米氮平代谢产物在人血浆中的浓度。实验中，研究毛细管区带电泳在进行生物样品分析时分离电压、流动相组成及缓冲液pH值对目标成份分析时间的影响，考察了进样方式、时间和电压、样品溶液中有机试剂的浓度对样品在线场放大技术的作用效果，同时比较了不同环糊精及其浓度对由于场放大作用导致的不对称峰形改善的效果及对手性药物拆分的效果。结果显示，在线场放大技术使得毛细管电泳-紫外检测法的灵敏度显著提高，能够满足生物样品检测的要求，并且缓冲液中添加合适的环糊精可以改善分析物的峰形，同时可以实现手性药物的拆分。将毛细管电泳技术和环糊精辅助的在线场放大技术联用，能有效地缩短了分析时间，提高了检测灵敏度，常规条件下即可实现临床生物样品的快速、灵敏、准确的分析。
药物代谢动力学是定量描述药物进入体内以后的吸收、分布、代谢、排泄过程，通过测定生物样本中的药物或者代谢产物的浓度，可以更好的阐明药物的药效或者毒性，为新药研究的代谢筛选和临床用药的安全有效提供重要依据。针对人血浆中的盐酸氨溴索，采用毛细管柱（长度31.2cm，内径75μm，有效长度21cm）进行分离分析，运行电压15kV，运行缓冲液为25mM磷酸二氢钠-6.25mM硼砂（10%磷酸调pH3.0）及1mM β-环糊精，电迁移进样7.5kV×15s，柱温25℃，紫外波长为210nm。采用96孔板液液萃取对200μL血浆进行样品前处理后进样分析，氨溴索和内标苯海拉明的保留时间分别为3.6和4.3分钟。与以往方法相比此法能够满足血药浓度测定的灵敏度同时缩短了分析时间，提高了样品分析的速度，测定结果和常规方法相当。
在很多手性药物中，对映体在生物利用度、对受体、转运体和/或酶的选择性、代谢速率、代谢产物及毒性等方面都有所差异，因此，对手性药物药代动力学的研究是有必要的。氨氯地平消旋体中，左旋和右旋氨氯地平的比例是1:1，但是只有左旋氨氯地平有药理活性。针对人血浆中的氨氯地平手性对映体，采用毛细管柱（长度31.2cm，内径75μm，有效长度21cm）进行分离分析，运行电压15kV，运行缓冲液为25mM磷酸二氢钠-6.25mM硼砂（10%磷酸调pH2.5）及30mg/mL羟丙基-β-环糊精，电迁移进样5kV×10s，柱温25℃，紫外波长为200nm。采用固相萃取对1mL血浆进行样品前处理后进样分析。血浆中氨氯地平手性对映体和内标苯海拉明的保留时间分别为5.7、6.2和6.7分钟。本实验建立了灵敏、快速、耗材少的毛细管电泳-紫外检测法用于测定临床生物样品中手性药物，实验数据与以往的方法无显著差异。
治疗药物监测是探讨患者体内血药浓度与疗效及毒性之间的关系，从而确定个体的最适治疗剂量及最佳用药方案，提高药物疗效和减少不良反应，其对于实现临床合理、安全用药有重要的意义。尤其在精神病学的临床运用中，对抗精神病药物进行治疗药物监测一直被认为是有重要意义的。左旋和右旋米氮平有不同的药动学及药效学参数，实验针对人血中米氮平及其代谢产物的手性对映体，采用毛细管柱（长度40.2cm，内径75μm，有效长度30cm）进行分离分析，运行电压17kV，运行缓冲液为25mM磷酸二氢钠-6.25mM硼砂（10%磷酸调pH2.5）及6.5mg/mL羧甲基-β-环糊精，电迁移进样7.5kV×10s，柱温25℃，紫外波长为200nm。采用96孔板液液萃取对300μL血浆进行样品前处理后进样分析，分析周期为8.5分钟。与现有的方法相比，该方法在体外能够同时测定米氮平及其三个代谢产物的对映异构体；在体内实验中，能够同时检测人血中米氮平对映体及其主要且具有药理活性的代谢物—N-去甲基-米氮平对映异构体，检测灵敏度能够满足血药浓度检测要求，分析时间较短，并成功的应用到了米氮平手性对映体的治疗药物检测研究中。
Clinical bio-sample analysis including metabolomics, therapeutic drug monitoring(TDM), pharmacokinetics and biochemical sample analysis is an important assistingmeans of clinical drug therapy. The method of bio-sample analysis compriseschromatography, spectroscopy, microbiological assay and immunoassay. Comparing withother three, chromatography combining their advantages is a more effective and accurateanalysis method. Common chromatography for the bio-sample assay is based on gaschromatography (GC), liquid chromatography (LC) or capillary electrophoresis (CE).
Recently, capillary electrophoresis (CE) has become a very important instrumentaltechnique in pharmaceutical and biological analysis because of its high separationefficiency in a short time and extremely low solvent consumption, while, the relativelypoor concentration sensitivity of CE when using UV detection due to the limited samplevolume and the short optical path length, limits CE application for sensitive detection ofbio-analysis. To solve the problem, field-amplified sample stacking (FASS) is usuallyemployed as a simple and efficient technique in capillary zone electrophoresis. It is basedon a mismatch between the electric conductivity of the sample and that of the runningbuffer. And when compared to injection from a nonstacking sample, conventional FASSprovided a significant sensitivity enhancement.
In our experiment, ambroxol, amlodipine and mirtazapine were selected as researchsubjects, scince all of them are effective in low dosage with a long half-life, and theirplasma concentration are very low. We try to establish capillary methods combined withon-line sample stacking for determination of ambroxol, amlodipine (enantiomers) andmirtazapine (enantiomers and those of the active metabolites) in human plasma. Theconditions of CE such as separation voltage, concentrations and pH of borate-phosphatebuffer were optimal to get the best running time. In addition, key parameters that affected-4- the stacking efficiency including injection modes, time and voltage, composition ofsample solvent were investigated to achieve higher sensitivity. Furthermore, type andconcentration of cyclodextrin were also studied to improve peak shape, resolution andcolumn efficiency or be employed as chiral selectors.
Pharmacokinetics is the study of the time course of a drug within the body andincorporates the processes of absorption, distribution, metabolism and excretion. To betterinterpret the effect and toxicity of the drug, an analytical method should be established todetermine the drug and its metabolites quantitatively, which help us to know about theirmechanisms of action and their pharmacokinetic properties during the initial state of drugdevelopment and in clinical therapy. In this paper, a β-cyclodextrin enhancedfield-amplified sample stacking (FASS) and capillary zone electrophoresis (CZE) methodis described for the quantification of ambroxol hydrochloride in human plasma，followingliquid-liquid extraction in the96-well format. The separation was carried out at25℃in a31.2cm×75μm fused-silica capillary with an applied voltage of15kV. The backgroundelectrolyte (BGE) was composed of6.25mM borate-25mM phosphate (pH3.0) and1mMβ-cyclodextrin. The sample was introduced by using electrokinetic (7.5kV×15s) injectionmodes. The detection wavelength was210nm. Under the above conditions the retentiontime of ambroxol hydrochloride and diphenhydramine (IS) was3.5and4.2min,respectively. Compared with those reported methods, the assay was time-saving andsensitive, and no difference was found between results of our method and the others.
In fact, the enantiomers of a chiral drug may differ significantly in their bioavailability,rate of metabolism, metabolites, excretion, potency and selectivity for receptors,transporters and/or enzymes, and toxicity. As a racemic mixture, racemic amlodipinecontains (R)-and (S)-amlodipine isomers in a1:1ratio, but only (S)-amlodipine as theactive moiety possesses therapeutic activity. Therefore, information about thepharmacokinetic behavior of the amlodipine enantiomers is necessary for understandingrelationships between drug levels and therapeutic response. In this study, a simple,sensitive and low-cost method using capillary electrophoresis coupled withhydroxypropyl-β-cyclodextrin interaction assisted acetonitrile field-amplified samplestacking technique for the quantitative enantioselective determination of trace drug (amlodipine, AML) was established for clinical applications. The separation wasperformed at25℃in a31.2cm×75μm fused-silica capillary with an applied voltage of15kV. The background electrolyte (BGE) was composed of6.25mM borate-25mMphosphate (pH2.5) and3mg/mL hydroxypropyl-β-cyclodextrin. The sample wasintroduced by using electrokinetic (7.5kV×15s) injection modes. The detectionwavelength was200nm. The retention time of amlodipine enantiomers anddiphenhydramine (IS) were5.7,6.2and6.7min, respectively.
Therapeutic drug monitoring (TDM) plays an important part in the optimal use of aselect few drugs. With the individualisation of drug therapy through measuredconcentrations the aim is to achieve maximum therapeutic response with minimal adverseeffects. And TDM is a constantly expanding practice in psychiatric clinics, mainly forantipsychotic agents. Mirtazapine is a chiral compound, however it is administeredclinically as a racemic mixture of S (+)-and R(-)-enantiomers. The two enantiomersdiffer in both pharmacokinetic and pharmacodynamic parameters. In this study, a simple,sensitive and environment-friendly method using capillary electrophoresis coupled withcarboxymethyl-β-cyclodextrin interaction assisted acetonitrile field-amplified samplestacking technique for the quantitative enantioselective determination of mirtazapine andits active demethylated metabolite in human plasma was established for clinicalapplications. The separation was performed at25℃in a40.2cm×75μm fused-silicacapillary with an applied voltage of17kV. The background electrolyte (BGE) wascomposed of6.25mM borate-25mM phosphate (pH2.5) and6.5mg/mLcarboxymethyl-β-cyclodextrin. The sample was introduced by using electrokinetic(7.5kV×10s) injection modes. The detection wavelength was200nm. The running timewas8.5min.
近几年，毛细管电泳作为一种新型的分离分析技术，较常规色谱有分析速度快、分离效能高，分析成本低，使用分析体系较其他色谱法更接近生物体液环境的优势，而越来越被重视，成为主流的生物样品分析方法。但当使用紫外检测器时，由于毛细管电泳的进样量和检测窗小，灵敏度受到限制。为了解决这个问题，场放大技术在毛细管电泳中起到了至关重要的作用。它主要原理是分析物在两个导电性不同的相界面上电泳速度的不同而形成富集效应，从而实现较高灵敏度的快速分离分析。
本课题选择盐酸氨溴索、苯磺酸氨氯地平及米氮平为研究对象，是因为它们给药剂量小，半衰期长，血药浓度低，希望通过建立合适的在线场放大毛细管电泳法，实现灵敏、快速、低耗的分离分析，并将其用于测定盐酸氨溴索、苯磺酸氨氯地平对映体及米氮平和米氮平代谢产物在人血浆中的浓度。实验中，研究毛细管区带电泳在进行生物样品分析时分离电压、流动相组成及缓冲液pH值对目标成份分析时间的影响，考察了进样方式、时间和电压、样品溶液中有机试剂的浓度对样品在线场放大技术的作用效果，同时比较了不同环糊精及其浓度对由于场放大作用导致的不对称峰形改善的效果及对手性药物拆分的效果。结果显示，在线场放大技术使得毛细管电泳-紫外检测法的灵敏度显著提高，能够满足生物样品检测的要求，并且缓冲液中添加合适的环糊精可以改善分析物的峰形，同时可以实现手性药物的拆分。将毛细管电泳技术和环糊精辅助的在线场放大技术联用，能有效地缩短了分析时间，提高了检测灵敏度，常规条件下即可实现临床生物样品的快速、灵敏、准确的分析。
药物代谢动力学是定量描述药物进入体内以后的吸收、分布、代谢、排泄过程，通过测定生物样本中的药物或者代谢产物的浓度，可以更好的阐明药物的药效或者毒性，为新药研究的代谢筛选和临床用药的安全有效提供重要依据。针对人血浆中的盐酸氨溴索，采用毛细管柱（长度31.2cm，内径75μm，有效长度21cm）进行分离分析，运行电压15kV，运行缓冲液为25mM磷酸二氢钠-6.25mM硼砂（10%磷酸调pH3.0）及1mM β-环糊精，电迁移进样7.5kV×15s，柱温25℃，紫外波长为210nm。采用96孔板液液萃取对200μL血浆进行样品前处理后进样分析，氨溴索和内标苯海拉明的保留时间分别为3.6和4.3分钟。与以往方法相比此法能够满足血药浓度测定的灵敏度同时缩短了分析时间，提高了样品分析的速度，测定结果和常规方法相当。
在很多手性药物中，对映体在生物利用度、对受体、转运体和/或酶的选择性、代谢速率、代谢产物及毒性等方面都有所差异，因此，对手性药物药代动力学的研究是有必要的。氨氯地平消旋体中，左旋和右旋氨氯地平的比例是1:1，但是只有左旋氨氯地平有药理活性。针对人血浆中的氨氯地平手性对映体，采用毛细管柱（长度31.2cm，内径75μm，有效长度21cm）进行分离分析，运行电压15kV，运行缓冲液为25mM磷酸二氢钠-6.25mM硼砂（10%磷酸调pH2.5）及30mg/mL羟丙基-β-环糊精，电迁移进样5kV×10s，柱温25℃，紫外波长为200nm。采用固相萃取对1mL血浆进行样品前处理后进样分析。血浆中氨氯地平手性对映体和内标苯海拉明的保留时间分别为5.7、6.2和6.7分钟。本实验建立了灵敏、快速、耗材少的毛细管电泳-紫外检测法用于测定临床生物样品中手性药物，实验数据与以往的方法无显著差异。
治疗药物监测是探讨患者体内血药浓度与疗效及毒性之间的关系，从而确定个体的最适治疗剂量及最佳用药方案，提高药物疗效和减少不良反应，其对于实现临床合理、安全用药有重要的意义。尤其在精神病学的临床运用中，对抗精神病药物进行治疗药物监测一直被认为是有重要意义的。左旋和右旋米氮平有不同的药动学及药效学参数，实验针对人血中米氮平及其代谢产物的手性对映体，采用毛细管柱（长度40.2cm，内径75μm，有效长度30cm）进行分离分析，运行电压17kV，运行缓冲液为25mM磷酸二氢钠-6.25mM硼砂（10%磷酸调pH2.5）及6.5mg/mL羧甲基-β-环糊精，电迁移进样7.5kV×10s，柱温25℃，紫外波长为200nm。采用96孔板液液萃取对300μL血浆进行样品前处理后进样分析，分析周期为8.5分钟。与现有的方法相比，该方法在体外能够同时测定米氮平及其三个代谢产物的对映异构体；在体内实验中，能够同时检测人血中米氮平对映体及其主要且具有药理活性的代谢物—N-去甲基-米氮平对映异构体，检测灵敏度能够满足血药浓度检测要求，分析时间较短，并成功的应用到了米氮平手性对映体的治疗药物检测研究中。
Clinical bio-sample analysis including metabolomics, therapeutic drug monitoring(TDM), pharmacokinetics and biochemical sample analysis is an important assistingmeans of clinical drug therapy. The method of bio-sample analysis compriseschromatography, spectroscopy, microbiological assay and immunoassay. Comparing withother three, chromatography combining their advantages is a more effective and accurateanalysis method. Common chromatography for the bio-sample assay is based on gaschromatography (GC), liquid chromatography (LC) or capillary electrophoresis (CE).
Recently, capillary electrophoresis (CE) has become a very important instrumentaltechnique in pharmaceutical and biological analysis because of its high separationefficiency in a short time and extremely low solvent consumption, while, the relativelypoor concentration sensitivity of CE when using UV detection due to the limited samplevolume and the short optical path length, limits CE application for sensitive detection ofbio-analysis. To solve the problem, field-amplified sample stacking (FASS) is usuallyemployed as a simple and efficient technique in capillary zone electrophoresis. It is basedon a mismatch between the electric conductivity of the sample and that of the runningbuffer. And when compared to injection from a nonstacking sample, conventional FASSprovided a significant sensitivity enhancement.
In our experiment, ambroxol, amlodipine and mirtazapine were selected as researchsubjects, scince all of them are effective in low dosage with a long half-life, and theirplasma concentration are very low. We try to establish capillary methods combined withon-line sample stacking for determination of ambroxol, amlodipine (enantiomers) andmirtazapine (enantiomers and those of the active metabolites) in human plasma. Theconditions of CE such as separation voltage, concentrations and pH of borate-phosphatebuffer were optimal to get the best running time. In addition, key parameters that affected-4- the stacking efficiency including injection modes, time and voltage, composition ofsample solvent were investigated to achieve higher sensitivity. Furthermore, type andconcentration of cyclodextrin were also studied to improve peak shape, resolution andcolumn efficiency or be employed as chiral selectors.
Pharmacokinetics is the study of the time course of a drug within the body andincorporates the processes of absorption, distribution, metabolism and excretion. To betterinterpret the effect and toxicity of the drug, an analytical method should be established todetermine the drug and its metabolites quantitatively, which help us to know about theirmechanisms of action and their pharmacokinetic properties during the initial state of drugdevelopment and in clinical therapy. In this paper, a β-cyclodextrin enhancedfield-amplified sample stacking (FASS) and capillary zone electrophoresis (CZE) methodis described for the quantification of ambroxol hydrochloride in human plasma，followingliquid-liquid extraction in the96-well format. The separation was carried out at25℃in a31.2cm×75μm fused-silica capillary with an applied voltage of15kV. The backgroundelectrolyte (BGE) was composed of6.25mM borate-25mM phosphate (pH3.0) and1mMβ-cyclodextrin. The sample was introduced by using electrokinetic (7.5kV×15s) injectionmodes. The detection wavelength was210nm. Under the above conditions the retentiontime of ambroxol hydrochloride and diphenhydramine (IS) was3.5and4.2min,respectively. Compared with those reported methods, the assay was time-saving andsensitive, and no difference was found between results of our method and the others.
In fact, the enantiomers of a chiral drug may differ significantly in their bioavailability,rate of metabolism, metabolites, excretion, potency and selectivity for receptors,transporters and/or enzymes, and toxicity. As a racemic mixture, racemic amlodipinecontains (R)-and (S)-amlodipine isomers in a1:1ratio, but only (S)-amlodipine as theactive moiety possesses therapeutic activity. Therefore, information about thepharmacokinetic behavior of the amlodipine enantiomers is necessary for understandingrelationships between drug levels and therapeutic response. In this study, a simple,sensitive and low-cost method using capillary electrophoresis coupled withhydroxypropyl-β-cyclodextrin interaction assisted acetonitrile field-amplified samplestacking technique for the quantitative enantioselective determination of trace drug (amlodipine, AML) was established for clinical applications. The separation wasperformed at25℃in a31.2cm×75μm fused-silica capillary with an applied voltage of15kV. The background electrolyte (BGE) was composed of6.25mM borate-25mMphosphate (pH2.5) and3mg/mL hydroxypropyl-β-cyclodextrin. The sample wasintroduced by using electrokinetic (7.5kV×15s) injection modes. The detectionwavelength was200nm. The retention time of amlodipine enantiomers anddiphenhydramine (IS) were5.7,6.2and6.7min, respectively.
Therapeutic drug monitoring (TDM) plays an important part in the optimal use of aselect few drugs. With the individualisation of drug therapy through measuredconcentrations the aim is to achieve maximum therapeutic response with minimal adverseeffects. And TDM is a constantly expanding practice in psychiatric clinics, mainly forantipsychotic agents. Mirtazapine is a chiral compound, however it is administeredclinically as a racemic mixture of S (+)-and R(-)-enantiomers. The two enantiomersdiffer in both pharmacokinetic and pharmacodynamic parameters. In this study, a simple,sensitive and environment-friendly method using capillary electrophoresis coupled withcarboxymethyl-β-cyclodextrin interaction assisted acetonitrile field-amplified samplestacking technique for the quantitative enantioselective determination of mirtazapine andits active demethylated metabolite in human plasma was established for clinicalapplications. The separation was performed at25℃in a40.2cm×75μm fused-silicacapillary with an applied voltage of17kV. The background electrolyte (BGE) wascomposed of6.25mM borate-25mM phosphate (pH2.5) and6.5mg/mLcarboxymethyl-β-cyclodextrin. The sample was introduced by using electrokinetic(7.5kV×10s) injection modes. The detection wavelength was200nm. The running timewas8.5min.
引文
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