【作者】 王丽；

【导师】 章竹君；

【作者基本信息】 陕西师范大学 ， 分析化学， 2005， 硕士

【摘要】 本文用毛细管电泳（CE）-微透析（MD）联用原位、在体、实时研究了市售的4种药物在家兔体内的药代动力学。考察了温度、透析速度、灌流液的组成对透析率的影响以及影响毛细管电泳分离的诸多因素,如:进样时间、分离电压、毛细管柱温、缓冲溶液的组成及pH值等。并对所测得的数据进行了药代动力学计算。全文共由两部分组成。 第一部分对毛细管电泳在药物测定和药代动力学研究及其与微透析联用在药代动力学中的应用进行了综述。 第二部分为实验部分,包括:Ⅰ.毛细管电泳法检测微透析液中的头孢唑林钠;Ⅱ.在体微透析采样技术与毛细管电泳联用研究马来酸曲美布汀在家兔体内的药代动力学;Ⅲ.微透析和毛细管电泳联用检测家兔血液中游离的美托洛尔浓度;Ⅳ.微透析与毛细管电泳联用持续监测家兔血液中的曲马多。 Ⅰ.毛细管电泳法检测微透析液中的头孢唑林钠 微透析（MD）与毛细管电泳（CE）相结合,监测了家兔血液中头孢唑林钠（Cefazolin sodium,CFZ）浓度的变化,并初步研究了CFZ的药代动力学。最佳电泳条件为:50mmol/L的硼砂（pH 9.5）缓冲液,20 kV分离电压,214nm紫外检测,环丙沙星为内标。在此条件下,CFZ测定的线性范围为1～300μg/mL,检出限为0.3μg/mL（3σ）。微透析灌流速度为3μL/min,探针透析率31.8±6.8%（n=3）。测定结果经NDST药动学软件分析,表明CFZ在家兔体内的清除半衰期为24.5min。 Ⅱ.在体微透析采样技术与毛细管电泳联用研究马来酸曲美布汀在家兔体内的药代动力学 在体微透析与毛细管电泳联用检测家兔血液中马来酸曲美布汀（TM）的浓度。以3μL/min的灌流速度灌注微透析探针,得到探针的透析率为26.64±3.1%（n=3）。最佳分析条件为:50mmol/L Tris-H₃PO₄缓冲液（pH 2.5）;毛细管内径50μm,有效长度40cm,毛细管温度25℃,压力进样10s,电压18kV,214nm UV检测。方法快速,电泳15min即可完成TM的有效分离和定量分析。在0.5-100μg/mL的浓度范围内线性良好（r=0.9994）,检测限为0.1μg/mL（S/N=3）。并研究了TM在家兔体内的药代动力学,血药浓度-时间数据经NDST药动学软件处理得到药代动力学参数。更多还原

【Abstract】 Microdialydsis sampling combined with capillary electrophoresis was applied to study the pharmacokinetics of four commercial drugs. The temperature, microdialysis flow rate, components of the perfusion fluid and the buffer, injection time, separation voltage et al were optimized. All data were calculated using pharmacokinetic soft ware.The thesis consists of two parts:Part one: The research works about Pharmaceutical applications of capillary electrophoresis in recent years; Capillary electrophoresis as a versatile tool for the pharmacokinetic study; The research works in recent years about the application of microdialysis and capillary in pharmacokinetic were reviewed.Part two is research reports which is composed of 4 components as follows: I. In situ、 in vivo、 real time monitoring the concentration of cefazolin sodium in rabbit plasma by microdialysis sampling and capillary electrophoresis with UV detection; II. Pharmacokinetic study of trimebutine maleate in rabbit blood using in vivo microdialysis coupled to capillary electrophoresis; III. Determination of unbound metoprolol in rabbit blood by microdialysis and capillary electrophoresis; IV. Microdialysis coupled with capillary electrophoresis for continuous monitoring of free tramadol in rabbit blood.I. In situ、 in vivo、 real time monitoring the concentration of cefazolin sodium in rabbit plasma by microdialysis sampling and capillary electrophoresis with UV detectionIn vivo determining the concentrations of cefazolin sodium (CFZ) in rabbit plasma at different time after an iv dose by microdialysis sampling (MD) coupled with capillary electrophoresis (HPCE-UV) was established. The running buffer was 50 mmol/L borax buffer (pH 9.5), the running voltage was 20 kV, and the wave length was 214 nm. Under the optimized conditions, with ciprofloxacin as internal standard (IS), separation of CFZ from IS and other components in the dialysate was achieved within 15 min, the response of CFZ in plasma dialysate was linear over the range of 1-300 μg/mL, the detection limit was 0.3 μg/mL (3σ). Using 9 nL as the injection volume, the corresponding mass detection limit was 2.7×10-12 g. The recovery of microdialysis probe was 31.8% andRSD was 6.8% (n=3) at the perfusion rate of 3 μL/min. All data was analyzed by NDST pharmacokinetic software, the half-life for CFZ in rabbit was 24.5 min.Ⅱ. Pharmacokinetic study of trimebutine maleate in rabbit blood using in vivo microdialysis coupled to capillary electrophoresisIn vivo microdialysis was used together with capillary electrophoresis (CE) to monitor the concentration of trimebutine maleate (TM) in rabbit blood. Dialysis probe was perfused at 3 μL/min resulting in relative recovery of 26.6 ±3.1% (n=3). After a one step sample preparation the samples were injected directly into the capillary. TM was detected on-column using UV detector at 214 ran. Separation of TM from other components in the dialysate was achieved within 15 min. Evaluation was based on the relative collected peak height (TM/IS). The response for TM in the blood dialysate was linear over the range of 0.5-100 μg/mL. The detection limit of TM in the blood dialysate was 0.1 μg/mL (S/N=3). This method has been successfully applied to the pharmacokinetic study of trimebutine maleate in rabbit blood following oral administration of 200 mg/kg. It provides a fast and simple technique for the pharmacokinetic study of TM in vivo.Ⅲ. Determination of unbound metoprolol in rabbit blood by microdialysis and capillary electrophoresis: A pharmacokinetic studyA microdialysis method followed by a capillary electrophoresis procedure has been performed for the assay of unbound metoprolol in rabbit blood. A microdialysis probe was inserted into the ear vein for blood sampling. The electrophoresis conditions were: 47(40) cm × 50 μm silica capillary, 50 mmol/L acetate pH 4.0, 10 s hydrodynamic load, detection wavelength 214 nm, run voltage18 kV, temperature 25 ℃. In vitro recoveries of microdialysis probes were determination and capillary electrophoresis resolution and detection were validated for response linearity as well as intra- and inter-day variabilities. The method was then applied to pharmacokinetics profiling of metoprolol in the blood following oral administration of metoprolol (60 mg/kg) in rabbits. Pharmacokinetics were calculated from the corrected data for dialysate concentrations of metoprolol versus time. This study demonstrated the applicability of this continuous sampling method for pharmacokinetic study.Ⅳ. Microdialysis coupled with capillary electrophoresis for continuous monitoring of free tramadol in rabbit bloodThis report describes a pharmacokinetic study protein-free tramadol in rabbit blood更多还原