目的 研究甲磺酸多沙唑嗪（Dox）缓释片在Beagle犬体内的药动学，评价其生物等效性。方法 8条健康Beagle犬，采用双周期、双交叉、单剂量分别ig Dox缓释片受试制剂或参比制剂4 mg；建立血浆中Dox液相色谱-质谱联用（LC-MS/MS）检测方法，进行方法精密度、准确度、回收率、基质效应、稳定性方法学验证；测定给药前（0 h）及给药后2、3、4、5、6、8、10、12、14、16、24、36、48、72 h血浆中Dox经时血药浓度，运用DAS3.2.8计算其药动学参数，并评价其生物等效性。结果 LC-MS/MS方法学经验证符合检测要求。主要药动学参数如下：受试制剂与参比制剂的C_max分别为（29.998 ±3.725）、（31.207 ±5.586） ng/mL，T_max分别为（11.5 ±2.33）、（11.25 ±1.035） h，AUC_0-t分别为（528.549 ±84.526）、（539.852±94.232） ng· h/mL；受试制剂AUC_0-t、AUC_0-∞和C_max的90%置信区间分别为参比制剂相应参数的84.6%~113.9%、88.6%~107.5%和90.2%~104%，均在80%~125%范围内。结论 Dox缓释片受试制剂与参比制剂生物等效。

Objective To develop a validated LC-MS/MS method for determining doxazosin mesylate (Dox) in Beagle dogs,and investigate the pharmacokinetic profiles and bioequivalence of Dox extended-release tablets.Methods Eight healthy Beagle dogs were ig given Dox sustained-release tablets or reference tablets of 4 mg in two-cycle,double-crossover and single-dose respectively.A method for the determination of Dox in plasma by LC-MS/MS was established.The method was validated for precision,accuracy,recovery,matrix effect and stability.The blood concentration of Dox in plasma was determined before (0 h) and 2,3,4,5,6,8,10,12,14,16,24,36,48,72 h after administration.The pharmacokinetic parameters were calculated by DAS 3.2.8 and its bioequivalence was evaluated.Results LC-MS/MS methodologies were verified to meet the detection requirements.The main pharmacokinetic parameters of Dox test and reference preparations after a single dose were as follows:C_max,(29.998 ±3.725) and (31.207 ±5.586) ng/mL;T_max,(11.5 ±2.33) and (11.25 ±1.035) h;AUC_0-t,(528.549 ±84.526) and (539.852 ±94.232) ng·h/mL;respectively.The 90% confidence intervals of AUC_0-t,AUC_0-∞ and C_max were respectively 84.6%~113.9%,88.6%~107.5% and 90.2%~104%,which were all within the range of 80%~125%.Conclusion Statistical analysis shows that Dox extended-release tablets was bioequivalent to reference tablets.

国家"重大新药创制"科技重大专项（2017ZX09201003-006）