美沙拉嗪缓释片单剂量与多剂量给药在Beagle犬体内的药动学研究
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篇名: 美沙拉嗪缓释片单剂量与多剂量给药在Beagle犬体内的药动学研究
TITLE:
摘要: 目的:建立测定Beagle犬血浆中美沙拉嗪血药浓度的方法,并用于美沙拉嗪缓释片在Beagle犬体内的药动学研究。方法:采用高效液相色谱-串联质谱法(HPLC-MS/MS)测定美沙拉嗪血药浓度。血浆样品加入水杨酸作为内标,经乙腈沉淀蛋白预处理;采用Inertsil ODS-3为色谱柱,乙腈-10 mmol/L乙酸铵溶液(含0.2%甲酸)(85 ∶ 15,V/V)为流动相;以电喷雾离子源(负离子模式)检测,多反应监测模式扫描,用于定量分析的离子对分别为m/z 152.0→107.9(美沙拉嗪)、m/z 137.0→92.9(内标)。取Beagle犬6只,单剂量(1.2 g)和多剂量(每天1.2 g,连续7 d)给予美沙拉嗪缓释片,采集各时间点血样,测定血浆中药物浓度。采用DAS 3.3.1数据处理软件计算不同给药方式下的药动学参数以及多剂量给药后的蓄积因子(R),并采用SPSS 16.0软件进行药动学参数的组间比较。结果:美沙拉嗪血药浓度在0.1~100 μg/mL范围内线性关系良好(r=0.999 1),定量下限为0.1 μg/mL;批内、批间精密度及基质效应试验的RSD均小于11%;相对误差(RE)为-0.75%~10.45%;提取回收率大于60%(RSD<5%);稳定性试验的RSD小于10%,RE在±15%范围内。单剂量、多剂量给予美沙拉嗪缓释片后,Beagle犬体内美沙拉嗪的达峰浓度(cmax)、达峰时间(tmax)、血药浓度-时间曲线下面积(AUC0-t、AUC0-∞)、滞留时间(MRT0-t)、滞留方差(VRT0-t)、清除率(CLz)、消除半衰期(t1/2z)差异均无统计学意义(P>0.05),多剂量给药的R均值小于1.01。结论:本方法准确、快速、灵敏、专属性强,适用于美沙拉嗪缓释片在Beagle犬体内的药动学研究;单剂量和多剂量给药后,美沙拉嗪在Beagle犬体内的药动学特征一致,且多剂量给药未导致药物蓄积现象的发生。
ABSTRACT: OBJECTIVE: To establish a method for the determination of mesalazine concentration in plasma of Beagle dogs, and to study the pharmacokinetics of Mesalazine sustained-release tablets in Beagle dogs. METHODS: HPLC-MS/MS method was used to determine the plasma concentration of mesalazine. Using salicylic acid as internal standard, after pre-treatment of acetonitrile precipitated protein, the determination was performed on Inertsil ODS-3 column with mobile phase consisted of acetonitrile-10 mmol/L ammonium acetate (containing 0.2% formic acid) solution (85 ∶ 15,V/V). ESI source (negative ion mode) detection was adopted in MRM mode, and the ion pair for quantity analysis were m/z 152.0→107.9 (mesalazine) and m/z 137.0→92.9 (internal standard). Six Beagle dogs were selected and given single dose (1.2 g) and multiple dose (1.2 g each day, for consecutive 7 d) of Mesalazine sustained-release tablets. Blood sample was collected at different time points, and plasma concentration was determined. DAS 3.3.1 software was used to calculate pharmacokinetic parameters of different doses administration and accumulation factor (R) of multiple dose administration. Pharmacokinetic parameters were compared by using SPSS 16.0 software. RESULTS: The linear range of mesalazine concentration were 0.1-100 μg/mL (r=0.999 1), and minimum quantification limit was 0.1 μg/mL. The RSDs of inter-batch and intra-batch precision and matrix effect were all less than 11%. Relative error (RE) of accuracy ranged -0.75%-10.45%; extraction recovery was higher than 60% (RSD<5%). RSDs of stability tests were lower than 10%, and RE was within ±15%. After administration of single dose and multiple dose, there was no statistical significance in peak concentration (cmax), peak time (tmax), area under curve of plasma concentration-time curve (AUC0-t, AUC0-∞), retention time (MRT0-t), retention variance (VRT0-t), clearance rate (CLz) or elimination half life (t1/2z) of mesalazine (P>0.05). The R of multiple dose was less than 1.01. CONCLUSIONS: The method is accurate, rapid, sensitive and specific, which is suitable for pharmacokinetic study of Mesalazine sustained-release tablets in Beagle dogs. After single dose and multiple dose administration,mesalazine has same pharmacokinetic characteristics in Beagle dogs, but no drug accumulation is found.
期刊: 2018年第29卷第16期
作者: 向荣凤,喻明洁,熊丽蓉,戴青,李晓宇,陈勇川
AUTHORS: XIANG Rongfeng,YU Mingjie,XIONG Lirong,DAI Qing,LI Xiaoyu,CHEN Yongchuan
关键字: 美沙拉嗪缓释片;高效液相色谱-串联质谱法;Beagle犬;药动学
KEYWORDS: Mesalazine substained-release tablets; HPLC- MS/MS; Beagle dog; Pharmacokinetics
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