[关键词]
[摘要]
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Cmax分别为(29.998 ±3.725)、(31.207 ±5.586) ng/mL,Tmax分别为(11.5 ±2.33)、(11.25 ±1.035) h,AUC0-t分别为(528.549 ±84.526)、(539.852±94.232) ng· h/mL;受试制剂AUC0-t、AUC0-∞和Cmax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。
[Key word]
[Abstract]
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:Cmax,(29.998 ±3.725) and (31.207 ±5.586) ng/mL;Tmax,(11.5 ±2.33) and (11.25 ±1.035) h;AUC0-t,(528.549 ±84.526) and (539.852 ±94.232) ng·h/mL;respectively.The 90% confidence intervals of AUC0-t,AUC0-∞ and Cmax 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.
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[基金项目]
国家"重大新药创制"科技重大专项(2017ZX09201003-006)