热痹清片中马钱子碱和士的宁在大鼠体内的药动学分析

Pharmacokinetics Analysis of Brucine and Strychnine from Rebiqing Tablets in Rats

目的：大鼠灌胃给予热痹清片和制马钱子粉后,计算马钱子碱和士的宁的药动学参数,比较二者在血浆中的药动学特征变化。方法：采用UPLC-MS/MS测定大鼠血浆中马钱子碱和士的宁的含量。Agela Venusil ASB C18色谱柱（2.1mm×50 mm,3μm）,流动相乙腈-0.15%甲酸溶液（60∶40）,柱温35℃,流速0.1 m L·min-1,进样量5μL。以盐酸克伦特罗为内标,采用ESI＋模式,多反应离子监测（MRM）,定量分析的离子分别为马钱子碱m/z 395.22~243.97,士的宁m/z 335.14~183.96,盐酸克伦特罗m/z 277.11~202.87。样品处理采用液液萃取法。利用DAS 2.1软件计算药动学参数。结果：热痹清片和制马钱子粉中马钱子碱的达峰时间（tmax）分别为（27±11）,（40±12）min,士的宁依次为（30±9）,（42±14）min,马钱子碱的药峰浓度（Cmax）分别为（5.6±1.2）,（4.5±1.7）μg·L-1,士的宁依次为（27.3±10.8）,（15.9±7.0）μg·L-1,马钱子碱的药时曲线下面积（AUC0-t）分别为（922±96）,（710±126）μg·min·L-1,士的宁依次为（3 957±651）,（2 031±256）μg·min·L-1,马钱子碱的清除率/生物利用的（CL/F）分别为（4 596±306）,（87±34）L·min-1·kg-1,士的宁依次为（880±84）,（49±10）L·min-1·kg-1。结论：马钱子碱和士的宁在大鼠体内药动学行为均符合二房室模型。与制马钱子粉比较,热痹清片能显著提高生物利用度,使其有效成分吸收、消除加快。

Objective： To calculate pharmacokinetic parameters of brucine and strychnine in rats after oral administration of Rebiqing tablets and Strychni Semen Pulveratum, and compare their pharmacokinetic characteristics in plasma. Method： UPLC-MS / MS was employed to determine contents of brucine and strychnine in rat plasma with Agela Venusil ASB C18column（ 2. 1 mm × 50 mm,3 μm）,taking acetonitrile-0. 15% formic acid（ 60 ∶ 40） as mobile phase at 0. 1 m L·min- 1. Column temperature was 35 ℃. Internal standard was clenbuterol hydrochloride, UPLC-MS / MS was performed with electrospray ionization（ ESI） and operated in positive mode in multiple reaction monitoring（ MRM）. Reaction selected ions were m / z 395. 22-243. 97 for brucine, m / z 335. 14-183. 96 for strychnine and m / z 277. 11-202. 87 for internal standard. Samples were extracted from rat plasma by liquid-liquid extraction. Pharmacokinetic parameters were calculated by DAS 2. 1software. Result： Main pharmacokinetic parameters of brucine in Rebiqing tablets and Strychni Semen Pulveratum were as follows： tmaxof（ 27 ± 11）,（ 40 ± 12） min,Cmaxof（ 5. 6 ± 1. 2）,（ 4. 5 ± 1. 7） μg·L- 1,AUC0-tof（ 922 ± 96）,（ 710 ± 126） μg·min·L- 1,CL/F of（ 4 596 ± 306）,（ 87 ± 34） L·min- 1·kg- 1; parameters of strychnine in them were（ 30 ± 9）,（ 42 ± 14） min,（ 27. 3 ± 10. 8）,（ 15. 9 ± 7. 0） μg·L- 1,（ 3 957 ± 651）,（ 2 031 ± 256） μg·min·L- 1and（ 880 ± 84）,（ 49 ± 10） L·min- 1·kg- 1, respectively. Conclusion：Pharmacokinetic behavior of brucine and strychnine are well fitted to two-compartment model in rats. Compared with Strychni Semen Pulveratum, Rebiqing tablets can significantly improve oral bioavailability, accelerate absorption and elimination rate of brucine and strychnine.