硝苯地平缓释片临床前药动学及生物利用度研究

目的研究硝苯地平缓释片在Beagle犬体内的药动学和生物利用度。方法采用双周期随机交叉试验设计,分别给予8只Beagle犬受试制剂（硝苯地平缓释片）或参比制剂（硝苯地平控释片）30mg,采用LC-MS/MS法测定给药后不同时间的血药浓度。选用DAS2.0软件计算药动学参数,并对药代参数进行配对t检验统计分析。结果血浆中硝苯地平线性范围为0.05～30ng/mL,最低定量限为0.05ng/mL,分析方法灵敏、准确、特异性高。受试制剂和参比制剂的峰浓度、达峰时间和药-时曲线下面积分别为（4.46±2.11）、（5.21±2.68）ng/mL,（11.0±3.85）、（7.38±2.97）h,（49.5±25.9）、（49.6±25.2）ng·h/mL。以药–时曲线下面积计算受试制剂的相对生物利用度为（104±43.5）%。结论建立的分析方法操作简单、准确、重复性好,可用于犬体内硝苯地平药动学和相对生物利用度的研究;受试制剂具有一定的延迟释放特征。

Preclinical study on pharmacokinetics and bioavailability of Nifedipine Sustained-release Tablets

Objective To study the pharmacokinetics （PK） and bioavailability of Nifedipine Sustained-release Tablets （NSRT） in Beagle’s dogs. Methods Using dicycle randomized crossover study, test tablets （NSRT） or reference tablets （Nifedipine Controlled-release Tablets, NCRT） with the dose of 30 mg were given to eight Beagle’s dogs. The plasma concentration of nifedipine collected at different time points was determined by LC-MS/MS method. The main PK parameters were obtained by DAS 2.0 program. Results With the linear range of 0.05—30 ng/mL and the lower limit quantification of 0.05 ng/mL, the LC-MS/MS method had high sensitivity, accuracy, and specificity. The main PK parameters of NSRT and NCRT were as follows： the Cmax were （4.46 ± 2.11） and （5.21 ± 2.68） ng/mL, the tmax were （11.0 ± 3.85） and （7.38 ± 2.97） h, and the AUC0-t were （49.5 ± 25.9） and （49.6 ± 25.2） ng·h/mL. Compared to NCRT, the bioavailability of NSRT was （104 ± 43.5）%. Conclusion The method is simple and accurate for the determination of the drug plasma concentration with good repeatability, and is successfully applied to the bioavailability evaluation of NSRT in Beagle’s dogs. The NSRT has the feature of sustained release.