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建立测定大鼠血浆中度洛西汀浓度的液相色谱-串联质谱法(LC-MS/MS),并比较研究度洛西汀在正常和糖尿病大鼠的药代动力学。以地西泮为内标,色谱柱为Waters Xterra~ RP18(100 mm×4.6 mm,3.5μm),以甲醇-含0.3%甲酸的5 mmol·L~(-1)醋酸铵水溶液(75∶25)为流动相,流速为0.6 m L·min~(-1),用电喷雾离子源,正离子多反应监测,分析时间5.5 min。度洛西汀血浆在10~5 000 ng·m L~(-1)浓度内线性关系良好。采用腹腔注射链脲佐菌素的方法建立糖尿病大鼠模型,与正常大鼠相同剂量(40 mg·kg~(-1))灌胃给予度洛西汀,于眼眶静脉丛采血测定血药浓度,用DAS软件计算药动学参数,用SPSS软件进行统计分析。主要药代动力学参数结果表明,糖尿病组:C_(max)为1 185±190.0 ng·m L~(-1)、AUC_(0-∞)为8 398±1 835 ng·m L~(-1)·h、t_(max)为1.6±0.4 h、t_(1/2z)为3.6±0.9 h;正常组:C_(max)为368.1±40.7 ng·m L~(-1)、AUC_(0-∞)为4 145±640.1 ng·m L~(-1)·h、t_(max)为1.6±0.3 h、t_(1/2z)为4.1±0.8 h。结果表明,度洛西汀在糖尿病模型大鼠体内的暴露量显著高于正常大鼠,约是正常大鼠的2倍。
To establish a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method for the determination of duloxetine in plasma of rats and to compare the pharmacokinetics of duloxetine in normal and diabetic rats. Using the internal standard of diazepam, the column was Waters Xterra ~ RP18 (100 mm × 4.6 mm, 3.5 μm). The methanol-aqueous 5 mmol·L -1 ammonium acetate solution containing 75% 25) as the mobile phase at a flow rate of 0.6 m L · min ~ (-1). Electrospray ionization (ESI) ion source was used to monitor the positive ions. The analysis time was 5.5 min. Duloxetine plasma had a good linear relationship at 10 ~ 5 000 ng · m L -1 concentration. The model of diabetic rats was established by intraperitoneal injection of streptozotocin. Duloxetine was administered intragastrically at the same dose (40 mg · kg -1) as that of normal rats, blood was collected at orbital venous plexus The pharmacokinetic parameters were calculated by DAS software and analyzed by SPSS software. The results of the main pharmacokinetic parameters showed that in the diabetic group, the C max was 1 185 ± 190.0 ng · m L -1 and the AUC 0- ∞ was 8 398 ± 1 835 ng · m L ~ (- 1) · h, t max was 1.6 ± 0.4 h and t 1 / 2z was 3.6 ± 0.9 h. In the normal group, C max was 368.1 ± 40.7 ng · m L -1 and AUC_ 0-∞) was 4 145 ± 640.1 ng · m L -1 · h, t ± max was 1.6 ± 0.3 h and t 1 / 2z was 4.1 ± 0.8 h. The results showed that the exposure of duloxetine in diabetic rats was significantly higher than that in normal rats, about twice that of normal rats.