摘要
目的:建立LC-MS/MS法,测定苯环喹溴铵血药浓度,考察其鼻喷雾剂以180μg剂量单次与多次给药后的人体药动学特征。方法:色谱采用Hedera ODS-2 C18柱(150 mm×2.1 mm,5μm),柱温为39℃,流动相为10 mmol.L-1醋酸铵溶液(含0.2%乙酸)-乙腈(67∶33),流速为0.60 mL.min-1,进样量为10μL;质谱采用电喷雾正离子化,多重反应监测,苯环喹溴铵和内标1-乙基-苯环喹溴铵的反应检测离子分别为m/z 330.2→142.1和m/z 344.2→156.1。11名健康受试者依次以180μg剂量进行苯环喹溴铵鼻喷雾剂单次与多次鼻腔给药的药动学试验,其中多次给药时间分别为每日上午7∶00早餐前、11∶00午餐前以及下午15∶00和晚间19∶00,并于给药间隔的若干时间点采集血样,血样经分离及固相萃取柱提取后进行LC-MS/MS分析。结果:分析方法学评价:苯环喹溴铵血药浓度在3.591～1 231 ng.L-1范围内线性关系良好,方法精密度、准确度和回收率均良好,且无明显介质效应干扰。药动学评价:与单次给药相比,受试者多次给药后,苯环喹溴铵的t1/2和Tmax均无显著差异(P>0.05),即苯环喹溴铵在人体内的药动学特征未发生明显变化,且无体内蓄积现象发生;多次给药至血药浓度达稳态后,每日4个给药间隔的最高血药浓度以及以Cmax和AUC计算的累积常数(>1)均逐步增大,即多次给药后苯环喹溴铵在人体内的暴露量与单次给药相比有所增加。结论:建立的LC-MS/MS法灵敏、快速,适用于苯环喹溴铵的血药浓度测定及药动学研究。苯环喹溴铵鼻喷雾剂以每日4次、每次180μg方案给药较为安全、合理。
Objective：To establish a LC-MS/MS method for the determination of bencycloquidium bromide（BCQB） in human plasma and to investigate the pharmacokinetics of its nasal spray following 180 μg single-and multiple-dose administration in healthy Chinese volunteers.Methods：A Hedera ODS-2 C18 column（150 mm × 2.1 mm,5 μm） at a column temperature of 39 ℃ and a mobile phase of 10 mmol ·L-1 ammonium acetate（containing 0.2% acetic acid）-acetonitrile（67：33）at a flow rate of 0.60 mL ·min-1 were used with an injection volume of 10 μL for LC;electrospray ionization（ESI） and positive multiple reaction monitoring（MRM） were used for MS,in which the reaction monitoring ions were m/z 330.2→142.1 for BCQB and m/z 346.2→156.1 for 1-ethyl bencycloquidium bromide as internal standard.Eleven healthy volunteers were administrated as a single dose（180 μg） and multiple doses（180 μg,qid,namely 7：00 am,11：00 am,3：00 pm and 7：00 pm daily） in turn with BCQB nasal spray in a pharmacokinetic trial.Blood samples were taken at different time points in dosing interval,separated,extracted with COOH-SPE and then analyzed by LC-MS/MS.Results：The established LC-MS/MS method was evaluated as follows：the calibration curve of BCQB in human plasma was linear over the range of 3.591-1 231 ng ·L-1,the precision,accuracy and recovery were good,and no significant matrix effect was found.The pharmacokinetics of BCQB nasal spray was evaluated as follows：there were no significant differences in t1/2 and Tmax,main pharmacokinetic profiles,of BCQB for multiple dosing compared with single dosing（P0.05）,indicating no significant accumulation of BCQB in the body after multiple dosing.The steady state Cmax and accumulation constants（1） calculated with Cmax and AUC for multiple dosing increased gradually with 4 dosing intervals daily,suggesting more exposure of BCQB in the body after multiple dosing compared with single dosing.Conclusion：The LC-MS/MS method is rapid,sensitive and suitable for the determination of BCQB in human plasma and its pharmacokinetic study.The multiple-dose administration（180 μg,qid） of BCQB nasal spray is safe and reasonable.
出处
《药学进展》
CAS
2013年第7期334-339,共6页
Progress in Pharmaceutical Sciences
基金
国家科技重大专项"重大新药创制"项目(No.2009ZX09102-059)
