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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 plasma concentrations of phenylcyclohexaquinimurol and to investigate the pharmacokinetic characteristics of human nasal sprays after single and multiple doses of 180μg. Methods: Hedera ODS-2 C18 column (150 mm × 2.1 mm, 5 μm) was used. The column temperature was 39 ℃ and the mobile phase was 10 mmol·L -1 ammonium acetate solution (containing 0.2% acetic acid) -acetonitrile ), Flow rate of 0.60 mL.min-1, injection volume of 10μL; mass spectrometry positive electrospray ionization, monitoring of multiple reactions, the detection of phenylcyclohexabromium and the internal standard 1-ethyl-benzene ring quinoline bromide reaction Ions were m / z 330.2 → 142.1 and m / z 344.2 → 156.1.11 healthy subjects were followed by 180μg dose of benzene quinoline bromide nasal spray single and multiple nasal administration pharmacokinetic test, The multiple administration times were 7:00 am daily before breakfast, 11:00 am before lunch, 15:00 pm and 19:00 evening, and blood samples were collected at several time points during the administration interval. Blood samples were separated and fixed Phase extraction column for LC-MS / MS after extraction. Results: Analytical methodological evaluation: The calibration curve was linear within the range of 3.591-1,231 ng · L-1, and the precision, accuracy and recovery of the method were good, and there was no obvious interference of the medium effect. Pharmacokinetic evaluation: Compared with a single administration, after repeated administration of the test, there was no significant difference (P> 0.05) between t1 / 2 and Tmax of phenylcyclohexabromonium Pharmacokinetic characteristics of the human body did not change significantly, and no accumulation of body occurred; multiple administration until the plasma concentration reached steady state, the maximum daily plasma concentration of 4 dosing interval and Cmax and AUC (> 1) increased gradually. That is to say, the release of phenylcyclohexaquinone in human after repeated administrations increased compared with that of single administration. Conclusion: The established LC-MS / MS method is sensitive, rapid and suitable for the determination of the concentration of phenylcyclohexa-quine bromide and pharmacokinetic study. Benzene ring quinoline bromide nasal spray 4 times a day, each 180μg program is more safe and reasonable administration.