摘要
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。
The study was aimed to establish a liquid chromatography - tandem mass spectrometric method for the determination of the duloxetine concentration in rat plasma, and compare the pharmacokinetics in normal and diabetes mellitus rat models. Diazepam was used as an internal standard. The separation was achieved on a Waters Xterra RP18 column （100 mm × 4.6 mm, 3.5 μm） with a mobile phase consisting of methanol - 0.3% formic acid containing 5 mmol.L^-1ammonium acetate （75 ： 25） at the flow rate of 0.6 mL.min-1. Electrospray ionization source was applied and operated in the positive multiple reaction monitoring mode. A good linearity of duloxetine was obtained in the concentration range of t 0-5 000 ng.mL-1. The rat models of diabetes mellitus were established by intraperitoneal injection of streptozotocin. The same dose of duloxetine （40 mg .kg-1） was given by intragastric administration to the normal and diabetic rats. Blood samples were collected from the orbital venous plexus to determinate duloxetine concentration in the plasma. The pharmacokinetic parameters were calculated by DAS software. Statistical analysis was performed by SPSS software. The major pharma- cokinetic parameters of diabetes group were as follows： Cmax was 1 185±190.0 ng.mL-1; AUC0-∞ was 8 398±1 835 ng.mL-1·h; /max was 1.6±0.4 h; h/2z was 3.6±0.9 h. The major pharmacokinetic parameters of normalgroup were as follows： Cmax was 368.1 ±40.7 ng·mL-1; AUC0-∞ was 4145±640.1 ng·mL-l·h; tmax was 1.6±0.3 h; t1/2z was 4.1± 0.8 h. The results of pharmacokinetic experiments suggest that the exposure amount of duloxetine in diabetic rats is twice higher than that in normal rats.
出处
《药学学报》
CAS
CSCD
北大核心
2017年第5期790-794,共5页
Acta Pharmaceutica Sinica
基金
苏州药学会-常州四药临床药学会科研基金(SYSD2015142)
江苏省自然科学基金-青年基金(BK20150302)
