尼达尼布在家兔体内的药动学研究

Study on Pharmacokinetics of Nintedanib in Rabbits

目的:建立家兔血浆尼达尼布检测的高效液相色谱方法,研究尼达尼布在家兔体内的药动学。方法:采用ZORBAX SB-C18色谱柱为分离柱,以乙腈-0.1%三氟乙酸-水(35∶20∶45)为流动相,流速为1.0 ml·min^(-1),检测波长为286 nm,柱温为35℃;以卡马西平为内标,血浆在碱性条件下经乙酸乙酯萃取后检测。雄性家兔6只,按20 mg·kg^(-1)的剂量耳缘静脉注射给予尼达尼布;分别在给药前和给药后不同时间点耳缘静脉采集血液,分离血浆待测。用DAS 3.0计算药动学参数。结果:尼达尼布浓度在0.05~10.00μg·ml^(-1)范围内线性关系良好(r=0.999 8);低中高三个浓度(0.10,2.50,7.50μg·ml^(-1))的日内精密度RSD分别为5.55%、4.53%和2.74%,日间精密度RSD分别为6.15%、5.45%和3.15%;相对回收率分别为(98.50±5.47)%、(100.25±4.54)%和(99.94±2.74)%。6只家兔血浆尼达尼布浓度经DAS 3.0计算,尼达尼布的主要药动学参数如下:C_(max)为(3.01±0.35)μg·ml^(-1),t_(1/2)为(4.38±1.53)h,AUC_(0-t)为(11.67±1.71)μg·h·ml^(-1)。结论:该方法简便、快速、准确,适用于家兔血浆尼达尼布浓度的测定及其药动学研究。尼达尼布在家兔体内呈一级动力学消除。

Objective： To develop an HPLC method for the determination of nintedanib in rabbit plasma and study the pharmacokinetics of nintedanib in rabbits. Methods： The separation was performed on an Agilent ZORBAX SB-C18 column. A mixture of acetonitrile-0. 1% trifluoroacetic acid-water（35∶ 20 ∶ 45） was used as the mobile phase at a flow rate of 1. 0 ml · min（-1）. The detection wavelength was set at 286 nm. Carbamazepine was used as the internal standard and nintedanib was extracted by ethyl acetate from plasma under basic condition. Totally 6 rabbits were given 20 mg·kg（-1）nintedanib with intravenous administration. The blood samples were collected from the auricular vein at different time points after the administration. The concentration of nintedanib in plasma was detected by the HPLC method. The pharmacokinetics parameters were analyzed by DAS program. Results： An excellent linear relationship was obtained within the range of 0. 05-10. 00 μg·ml（-1）（r = 0. 999 8）. The intra-day RSD was 5. 55%,4. 53% and 2. 74%and inter-day RSD was 6. 15%,5. 45% and 3. 15%,respectively for the three concentrations（0. 10,2. 50 and 7. 50 μg·ml（-1））,and the relative recovery was（98. 50 ± 5. 47） %,（100. 25 ± 4. 54） % and（99. 94 ± 2. 74） %,respectively. The main pharmacokinetics parameters of nintedanib were as follows： C_（max）was（3. 01 ± 0. 35） μg·ml（-1）,t_（1 /2）was（ 4. 38 ± 1. 53） h and AUC_（0-t）was（ 11. 67 ±1. 71） μg·h·ml（-1）. Conclusion： The method is simple,rapid and accurate,and can be used to determine the nintedanib concentration in rabbit plasma and study its pharmacokinetics. Nintedanib is fitted the first-order elimination kinetics in rabbits.