米拉贝隆缓释片在Beagle犬体内的药动学研究

Pharmacokinetics of Mirabegron Sustained-Release Tablets in Beagle Dogs

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×50mm，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1～1000ng·mL^-1内线性关系良好（r=0．9974），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·mL^-1；tmax分别为（3．72±1．87）和（4．64±1．55）h；AUC0→48分别为（1021±439）和（989±299）ng·h·mL^-1；AUC0→∞分别为（1043±441）和（1010±301）ng·h·mL^-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, sensitive method of liquid chromatographic-tandem mass spectrometric （LC-MS/ MS） for determination of mirabegron in dog plasma, and to evaluate the pharmacokinetics for single dose of different formulations of mirabegron sustained-release tablets in dogs. METHODS The analyte mirabegron and internal standards （IS） tolbutamide were separated on a BEH C18 column （2.1mm×50mm,1.7μm） with mobile phase of 0. 1% formic acid water solution-0. 1% formic acid methyl cyanides solution using a gradient elution mode at a flow rate of 450 μL·min^-1. In accordance with randomized two-period self crossover study, eight dogs were given single oral dose of the test preparation and reference preparation, then the concentration of mirabegron in plasma was determined, the pharmacokinetic parameters were calculated and the difference of the two preparations were evaluated. RESULTS The linear range of mirabegron in Beagle dogs plasma was 1 - 1 000 ng · mL^-1. The accuracy and the precisions of intra-day and inter-day also were qualified. After a single dose administration of the test preparation and reference preparation, the pharmacokinetic parameters were as follow： t1/2 were （ 7. 14 ±1.59 ） vs （ 7. 13 ±1.78 ） h, ρmax, were （ 144. 4 ± 77. 5 ） vs （ 130. 3 ± 39. 2 ） ng · mL^-1 , tmax were （3.72 ±1.87） vs （4. 64 ±1.55）h, AUC0→48 were （ 1 021 ±439） vs （989 ±299） ng · h · mL^-1 , AUC0→∞ were （1 043 ±441 ） vs （1 010 ±301 ）ng· h · mL^-1. CONCLUSION The LC-MS/MS method is suitable for pharmacokinetic study of mirabegron. Moreover, there is no significant difference in the pharmacokinetic profiles between the two preparations of mirabegron.