尼群地平微丸家犬体内药动学研究

Pharmacokinetics of nitrendipine pellets in healthy dogs

目的 研究自制尼群地平速释、缓释微丸在家犬体内的药物动力学,并进行相对生物利用度评价.方法 分别以尼群地平国产片和日本片为参比制剂,采用高效液相色谱法测定4个制剂的家犬体内血浆药物浓度并绘制平均血药浓度-时间曲线,计算药动学参数并进行方差分析,同时对自制制剂的生物利用度进行了评价.结果 尼群地平速释微丸、缓释微丸、国产片和日本片的Tmax依次为0.92±0.14、5.0、1.83±0.29和1.08±0.38h;Cmax依次为187.01±21.23、85.25±13.80、88.31±8.65和160.22±24.34ng·mL-1;AUC0～t依次为665.54±109.07、606.47±130.68、472.44±89.44和659.16±100.05 ng·h·mL-1.以国产片为参比制剂时,自制速释微丸和缓释微丸的相对生物利用度分别为146.92%和135.92%;以日本片为参比制剂时,速释微丸和缓释微丸的相对生物利用度分别为101.04%和91.63%.结论 自制速释微丸接近同类产品国外制剂,优于国内制剂;缓释微丸体内作用时间延长,但生物利用度偏低,需进一步改进处方或工艺.

OBJECTIVE To study the pharmacokinetics of nitrendipine immediate-release and sustained-release pellets,and evaluate the relative bioavailability in dogs.METHODS Following oral administration of a single dose of the nitrendipine immediate-release and sustained-release pellets as test formulations,and domestic tablets and Japanese tablets as reference formulations,drug in plasma was determined by HPLC and the plasma concentration-time curves of these formulations were obtained.The pharmacokinetic parameters were calculated and analyzed by ANOVA,and subsequently the relative bioavailabilities of two test formulations were evaluated.RESULTS The pharmacokinetic parameters of immediate-release pellets,sustained-release pellets,domestic tablets and Japanese tablets of nitrendipine were as below in turn:Tmax were 0.92±0.14,5.0,1.83±0.29 and 1.08±0.38h,respectively.Cmax were 187.01±21.23,85.25±13.80,88.31±8.65 and 160.22±24.34ng·mL-1,respectively.AUC0～t were 665.54±109.07,606.47±130.68,472.44±89.44 and 659.16±100.05ng·h·mL-1,respectively.The relative bioavailabilities of immediate-release pellets and sustained-release pellets were 146.92% and 135.92% compared with domestic tablets.However,the relative bioavailabilities of the two formulations were 101.04% and 91.63% respectively in comparison with Japanese tablets.CONCLUSION The quality of immediate-release nitrendipine pellets was equal to Japanese tablets and prior to the domestic tablets.Compared with two reference formulations,the sustained-release nitrendipine pellets have longer action time in dogs,however,a lower bioavailability was also found,which suggesting that the formulation or processing of the sustained-release pellets should be optimized in future.