目的 研究甲磺酸多沙唑嗪（Dox）緩釋片在Beagle犬體內(nèi)的藥動學(xué)，評價其生物等效性。方法 8條健康Beagle犬，采用雙周期、雙交叉、單劑量分別ig Dox緩釋片受試制劑或參比制劑4 mg；建立血漿中Dox液相色譜-質(zhì)譜聯(lián)用（LC-MS/MS）檢測方法，進行方法精密度、準(zhǔn)確度、回收率、基質(zhì)效應(yīng)、穩(wěn)定性方法學(xué)驗證；測定給藥前（0 h）及給藥后2、3、4、5、6、8、10、12、14、16、24、36、48、72 h血漿中Dox經(jīng)時血藥濃度，運用DAS3.2.8計算其藥動學(xué)參數(shù)，并評價其生物等效性。結(jié)果 LC-MS/MS方法學(xué)經(jīng)驗證符合檢測要求。主要藥動學(xué)參數(shù)如下：受試制劑與參比制劑的C_max分別為（29.998 ±3.725）、（31.207 ±5.586） ng/mL，T_max分別為（11.5 ±2.33）、（11.25 ±1.035） h，AUC_0-t分別為（528.549 ±84.526）、（539.852±94.232） ng· h/mL；受試制劑AUC_0-t、AUC_0-∞和C_max的90%置信區(qū)間分別為參比制劑相應(yīng)參數(shù)的84.6%~113.9%、88.6%~107.5%和90.2%~104%，均在80%~125%范圍內(nèi)。結(jié)論 Dox緩釋片受試制劑與參比制劑生物等效。

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.

國家"重大新藥創(chuàng)制"科技重大專項（2017ZX09201003-006）