尼群地平可生物降解微球和原位凝胶的药物动力学

Pharmacokinetics of nitrendipine biodegradable microspheres and in situ forming gel

目的研究尼群地平可生物降解微球和原位凝胶在家兔体内的药物动力学特征。方法采用HPLC法，测定3只健康家兔肌注尼群地平微球及原位凝胶（分别为受试制剂A、B）和尼群地平溶液（参比制剂C）后不同时间点的血药浓度，绘制药时曲线，计算药物动力学参数及相对生物利用度。结果家兔肌注相当于尼群地平30mg的制剂A、B和C后，血浆中尼群地平的tmax分别为3、1和1h；cmax分别为（468±30）、（2259±272）和（2777±445）nmol·L^-1；用梯形法计算，AUC0～t分别为（1193±249）、（1716±268）和（2257±199）nmol·d·L^-1. 与参比制剂C相比，受试制剂A、B的相对生物利用度分别为（52．15±11．54）％和（76．37±14．00）％。InAUC0～t在制剂A和C间有显著性差异。在B和C、A和B之间无显著性差异，在个体间均无显著性差异（P〉0．05），受试制剂A和B的AUC0～t90％置信区间分别为参比制剂的23．85％～110．57％和39．15％～145．75％。结论尼群地平可生物降解微球和原位凝胶与尼群地平溶液相比，在家兔体内具有更长的作用时间，但相对生物利用度较低。

Objective To study the pharmacokinetic characters of nitrendipine biodegradable microspheres and in situ forming gel. Methods After muscular injection administration of a single dose of nitrendipine biodegradable microspheres, in situ forming gel（test formulation A and B）and nitrendipine solution （reference formulation C） to each of three healthy rabbits, the plasma concentrations of the active drugs at different times were observed by HPLC and the plasma concentration-time curves of these formulations were obtained. The pharmacokinetic parameters and the relative bioavailabilities were calculated. Results After giving the dose of 30 mg, the tmax, values of the three formulations were 3, 1 and 1 h, the Cmax values were （468 ±30）, （2259 ±272） and （2777 ±445） nmol· L^-1, the AUC0-t were （1193± 249）, （1716 ± 268） and （2257 ± 199） nmol· d· L^- 1, respectively. The relative bioavailabilities of the test formulation A and B comparing with the reference formulation were （52.15 ± 11.54） % and （76.37 ± 14.00） %, respectively. The results of the variance analysis showed that there were no differences between formulation B and C, A and B, and in subjects（P 〉0.05）;However, significant difference was observed between formulation A and C. The 90 % confidence intervals of AUC0- t of the test formulation A and B comparing with the reference formulation were 23.85 % - 110.57 % and 39.15 % - 145.75 %, respectively. Conclusions Comparing with nitrendipine solution, nitrendipine biodegradable microspheres and in situ forming gel had longer action time in rabbits, but their relative bioavailabilities were lower.