盐酸美金刚缓释胶囊在比格犬体内的药动学研究

Pharmacokinetics of Memantine Hydroehloride Sustained-release Capsules in Beagle dogs

目的建立LC-MS/MS法研究盐酸美金刚缓释胶囊在比格犬体内的药动学特征。方法采用Agilent Extend-C18色谱柱(30 mm×4.6 mm,1.8μm);流动相A为0.1%甲酸,流动相B为甲醇,流动相B比例为65%,等度洗脱2.5 min;体积流量为1 mL/min,柱温40℃;进样量5μL。采用电喷雾离子源(ESI),多级反应监测(MRM)模式,以正离子化方式进行检测,用于定量分析的离子反应分别为m/z 180.0→107.0(盐酸美金刚)、m/z 268.0→116.0(内标琥珀酸美托洛尔)。将6只比格犬随机分为两组,采用两种制剂双周期交叉给药方法,分别ig盐酸美金刚缓释胶囊受试制剂或参比制剂1粒。采用LC-MS/MS法测定比格犬体内盐酸美金刚血药浓度。采用DAS ver 2.1.1软件进行数据分析并计算出相关药动学参数。结果盐酸美金刚的线性范围为1.25~125 ng/mL,定量下限为1.25 ng/mL,日内、日间精密度RSD值均小于6.5%。单次ig受试制剂和参比制剂后,比格犬血浆中盐酸美金刚的Cmax分别为(59.99±14.78)、(64.79±16.26)ng/mL,tmax分别为(7.83±2.64)、(7.33±3.5)h,t1/2分别为(10.84±2.04)、(11.39±1.31)h,AUC0-t分别为(9.99±3.3)、(11.02±2)μg·h/mL,AUC0-∞分别为(10.63±3.42)、(11.72±2.13)μg·h/mL。结论采用LC-MS/MS方法操作简单、准确度、专属性高,可用于盐酸美金刚缓释胶囊的药动学研究,盐酸美金刚受试制剂在比格犬体内药动学行为与参比制剂相似。

Objective To establish an LC-MS/MS method to study the pharmacokinetic characteristics of Memantine Hydrochloride Sustained-release Capsules in Beagle dogs. Methods The separation was performed on Agilent Extend-C18 column(30 mm × 4.6 mm, 1.8 μm). The mobile phase consisted of mobile phase A 0.1% formic acid and mobile phase B methanol, with 65% methanol isocratic elution for 0 - 2.5 min. The flow rate was 1.0 mL/min, temperature of column was set at 40 ℃, and volume of injection was 5 μL. Electrospray ionization(ESI) source and multiple-reaction monitoring(MRM) was performed in the positive ion mode. The ion pairs used for quantitative analysis were m/z 180.0→107.0(memantine hydrochloride) and m/z 268.0→116.0(internal standard metoprolol succinate). 6 Beagle dogs were randomly divided into two groups, and two preparations were administered in a two-cycle cross-over manner. Beagle dogs in two groups were ig administered with test preparation or reference preparation 1 tablet of Memantine Hydroehloride Sustained-release Capsules, respectively. The plasma concentration of memantine hydrochloride in Beagles was determined by LC-MS/MS method. And the pharmacokinetic parameters were calculated by DAS ver 2.1.1 Software. Results The linear range of memantine hydrochloride was 1.25 - 125 ng/mL, and the quantitative limits was 1.25 ng/mL. The RSD values of inter-day and intra-day precisions were less than 6.5%. After single ig administration with test and reference preparations, the Cmax of memantine hydrochloride in Beagle dogs plasma were(59.99 ± 14.78) and(64.79 ± 16.26) ng/mL, tmax were(7.83 ± 2.64) and(7.33 ± 3.5) h, t1/2 were(10.84 ± 2.04) and(11.39 ± 1.31) h, AUC0-t were(9.99 ± 3.3) and(11.02 ± 2)μg·h/mL, AUC0-∞ were(10.63 ± 3.42) and(11.72 ± 2.13)μg·h/mL. Conclusion LC-MS/MS method is simple, accurate, and specific. It can be used for pharmacokinetic study of Memantine Hydroehloride Sustained-release Capsules. The pharmacokinetic behavior of memantine hydroehloride tested preparation in Beagle dogs is similar to that of the reference preparation.