非洛地平缓释片在健康人体内的药动学研究  

Study on the Pharmacokinetics of Felodipine Sustained-release Tablets in Healthy Volunteers

作　　者：张圆[1] 张楠[1] 朱婷婷[1] 丁娅[1] 杭太俊[1] 陶蕾 李琳珺[2] 马鹏程[2] 

机构地区：[1]中国药科大学药物分析教研室,江苏南京210009 [2]中国医学科学院皮肤病研究所,江苏南京210042

出　　处：《药学进展》2013年第3期131-137,共7页Progress in Pharmaceutical Sciences

基　　金：中央高校基本科研业务费专项资金(No.JKP2011008);青蓝工程;新世纪优秀人才支持计划资助项目(No.NCET-10-0816)

摘　　要：目的:建立用于测定人血浆中非洛地平的LC-MS/MS法,研究非洛地平缓释片在健康人体内的药动学。方法:色谱条件:色谱柱为Agilent HC C18柱(150 mm×4.6 mm,5μm),流动相为甲醇-0.05%甲酸溶液(83∶17)和乙腈,线性梯度洗脱,流速为1 mL.min-1,柱温为35℃,进样量为20μL;质谱条件:电喷雾正离子化,三重四极杆质谱多反应监测模式,非洛地平和内标西尼地平的选择性反应检测离子分别为m/z 384.0→338.1和m/z 493.0→375.1。20名中国成年健康男性受试者随机分为2组,采用自身双交叉试验设计,先单剂量空腹口服5 mg非洛地平缓释片受试制剂或参比制剂,并于不同时间点采集肘静脉血(0～72 h);随后进行多剂量试验,2组受试者连续8 d服用受试制剂或参比制剂(5 mg,qd),于第8 d服药后按单剂量试验中的采血方案在各时间点采集血样。对采集的所有血样进行血浆分离及处理,采用建立的LC-MS/MS法测定非洛地平血药浓度,用DAS2.0软件计算药动学参数。结果:分析方法学评价:非洛地平血药浓度在0.025～10μg.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,且无明显基质效应。药动学评价:受试制剂单剂量和多剂量给药后的主要药动学参数Cmax分别为(1.29±0.49)和(1.26±0.48)mg.L-1以及AUC0-72 h分别为(21.2±5.0)和(20.1±7.9)mg.h.L-1,均与参比制剂无显著差异(P>0.05);与单剂量给药相比,2种制剂经多剂量给药后的稳态Cmax、Tmax和AUC值均无显著性变化。结论:建立的LC-MS/MS法专属、灵敏、准确,可满足非洛地平缓释片的药动学研究要求;非洛地平缓释片多剂量给药,不会导致体内药物蓄积。Objective： To establish a LC-MS/MS method for the determination of felodipine in human plasma to investigate the pharmacokinetics of felodipine sustained-release tablets in healthy volunteers.Methods： An Agilent HC C18column （150 mm ×4. 6 mm, 5 μm） at a column temperature of 35 ℃ and a mobile phase consisting of methanol-0. 05% formic acid （ 83 ： 17） and acetonitrile by linear gradient elution at a flow rate of 1 mL·min- 1 were used with an injection volume of 20 μL for LC. The positive ESI and MRM mode were used for triple quadrupole MS, in which the selected reaction monitoring ions were m/z 384. 0→338. 1 for felodipine and m/z 493.0→375. 1 for cilnidipine as the internal standard. In the randomized, crossover study, twenty healthy male Chinese volunteers were divided into 2 groups and were given a single oral dose of 5 mg felodipine sustained-release tablets （ test or reference formulation） after an overnight fast, followed by collecting cubital venous blood samples at different time points（O-72 h）. Subsequently, the volunteers were given multiple oral doses（ 5 mg, qd, for 8 d） of test or reference formulation and the blood samples were collected in the same way on day 8. All the blood samples after plasma separation and extraction were determined by the established LC-MS/MS method and the pharmacokinetic parameters of felodipine were calculated by DAS2. 0 software. Results： The established LC-MS/MS method was evaluated as follows： the calibration curve of felodipine in human plasma was linear in the range of O. 025-10 μg·L-1, the precision, accuracy and recovery were good, and no significant matrix effect was found. The pharmacokinetics of felodipine sustained-release tablets were evaluated as follows： Cmax and AUC0-72,the main pharmacokinetic parameters, for test formulation were （ 1.29± 0. 49） mg· L - 1and （21.2 ±5.0） mg·h·L-1 for single oral dose and （ 1.26 ±0. 48） mg·L-1 and （20. 1 ±7.9） mg·h·L-1 for multiple oral doses（ P 〉 0. 05,

关 键 词：非洛地平缓释片 高效液相色谱-串联质谱法 血药浓度 药动学 

分 类 号：R969.1[医药卫生—药理学] R972.4[医药卫生—药学]