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目的建立一种简便、灵敏的测定Beagle犬口服米拉贝隆缓释片自制品及市售品后的血浆药物浓度的液-质联用方法(LC-MS/MS),评价米拉贝隆缓释片自制品与市售品的药动学特征差异。方法以甲苯磺丁脲为内标,BEH C18色谱柱(2.1mm×50 mm,1.7μm),以0.1%甲酸水溶液与0.1%甲酸乙腈溶液梯度洗脱进行分离,流速为450μL·min-1。采用随机双交叉自身对照试验设计,8只Beagle犬单次交叉口服米拉贝隆缓释片自制品、市售品后测定血药浓度,计算药动学参数,评价两制剂的药动学差异。结果米拉贝隆在犬血浆中质量浓度在1~1 000 ng·m L-1内线性关系良好(r=0.997 4),准确度和精密度均符合生物样品分析要求。单剂量交叉给药后米拉贝隆缓释片自制品与市售品主要的药动学参数:t1/2分别为(7.14±1.59)和(7.13±1.78)h;ρmax分别为:(144.4±77.5)和(130.3±39.2)ng·m L-1;tmax分别为(3.72±1.87)和(4.64±1.55)h;AUC0→48分别为(1 021±439)和(989±299)ng·h·m L-1;AUC0→∞分别为(1 043±441)和(1 010±301)ng·h·m L-1。结论本测定方法可用于米拉贝隆Beagle犬体内药动学研究,且自制品和市售品在Beagle犬体内药动学行为没有显著差异。
Objective To establish a simple and sensitive LC-MS / MS method for the determination of plasma drug concentration of Beagle dog oral Mirabelon sustained-release tablets and its commercial products, Differences of pharmacokinetics between sustained release tablets and commercial products. Methods Tolbutamide was used as the internal standard and separated on a BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with a gradient of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The flow rate was 450 μL · min-1. Randomized double-crossover self-controlled trial design, 8 Beagle dogs oral cross-oral mirabeieron sustained-release tablets of homemade products, the determination of plasma concentrations of drugs, pharmacokinetic parameters were calculated to evaluate the differences between the two formulations . Results Mirabelone showed good linearity (r = 0.997 4) in the range of 1-1000 ng · m L-1 in the plasma of dogs, which met the requirements of biological samples analysis. The main pharmacokinetic parameters of milabelong sustained-release tablets after single-dose oral administration were (7.14 ± 1.59) and (7.13 ± 1.78) h respectively; ρmax were (144.4 (130 ± 39.2) ng · m L -1; tmax was (3.72 ± 1.87) and (4.64 ± 1.55) h respectively; AUC0 → 48 were (1021 ± 439) and (989 ± 299) ng · H · m L-1; AUC0 → ∞ were (1 043 ± 441) and (1 010 ± 301) ng · h · m L-1, respectively. Conclusion The method can be used to study the pharmacokinetics of milbe-berlin Beagle dogs. There is no significant difference in the pharmacokinetics between homemade and commercial products in Beagle dogs.