甲磺酸多沙唑嗪缓释片Beagle犬体内药动学和生物等效性研究
|
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。
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 Cmaxwere respectively 84.6% ～ 113.9%, 88.6% ～ 107.5% and90.2% ～ 104%, which were all within the range of 80% ～ 125%. Conclusion Statistical analysis shows that Dox extended-release tablets was bioequivalent to reference tablets.
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 Cmaxwere respectively 84.6% ～ 113.9%, 88.6% ～ 107.5% and90.2% ～ 104%, which were all within the range of 80% ～ 125%. Conclusion Statistical analysis shows that Dox extended-release tablets was bioequivalent to reference tablets.
引文
[1]赵颖.甲磺酸多沙唑嗪控释制剂的研究[D].沈阳:沈阳药科大学, 2004.
[2]刘可,钟大放,袁涛,等.多沙唑嗪人体药动学和肝微粒体中代谢的立体选择性研究[A].第九届全国药物和化学异物代谢学术会议.第九届全国药物和化学异物代谢学术会议论文集[C]. 2012.
[3]王雪姣.甲磺酸多沙唑嗪微孔渗透泵片的研制[D].石家庄:河北医科大学, 2009.
[4]薛娜.甲磺酸左旋多沙唑嗪的质量控制及药代动力学研究[D].石家庄:河北医科大学, 2007.
[5]化学药物非临床药代动力学研究技术指导原则[S].2005.
[6]中国药典[S].一部. 2015.
[7]张毕奎,朱运贵,谢平,等. HPLC-MS测定人血浆中多沙唑嗪及其在健康人体药动学研究中的应用[J].药物分析杂质, 2007, 27(9):1357-1360.
[8]王侠. LC-MS法检测甲磺酸多沙唑嗪控释片在中国男性健康志愿者中的相对生物利用度[J].现代泌尿外科杂质, 2008, 2:152.
[9]谢平,张比奎,朱运贵,等.甲磺酸多沙唑嗪片的人体药动学研究[J].中国医院药学杂志, 2006, 26(8):940-942.
[10]吕伟伟,孙成春,孙军,等.甲磺酸多沙唑嗪片在健康人体内的生物等效性研究[J].中国药房, 2009, 20(32):2514-2516.
[11]国家药典委员会.生物样品定量分析方法验证指导原则(中华人民共和国药典二部2015年版)[M].北京:化学工业出版社, 2015.
[12]师健鑫,卢骏,冯岩,等.甲磺酸多沙唑嗪单层渗透泵控释片的研制及Beagle犬体内的药动学[J].中国医药工业杂质, 2011, 42(5):347-350.
[2]刘可,钟大放,袁涛,等.多沙唑嗪人体药动学和肝微粒体中代谢的立体选择性研究[A].第九届全国药物和化学异物代谢学术会议.第九届全国药物和化学异物代谢学术会议论文集[C]. 2012.
[3]王雪姣.甲磺酸多沙唑嗪微孔渗透泵片的研制[D].石家庄:河北医科大学, 2009.
[4]薛娜.甲磺酸左旋多沙唑嗪的质量控制及药代动力学研究[D].石家庄:河北医科大学, 2007.
[5]化学药物非临床药代动力学研究技术指导原则[S].2005.
[6]中国药典[S].一部. 2015.
[7]张毕奎,朱运贵,谢平,等. HPLC-MS测定人血浆中多沙唑嗪及其在健康人体药动学研究中的应用[J].药物分析杂质, 2007, 27(9):1357-1360.
[8]王侠. LC-MS法检测甲磺酸多沙唑嗪控释片在中国男性健康志愿者中的相对生物利用度[J].现代泌尿外科杂质, 2008, 2:152.
[9]谢平,张比奎,朱运贵,等.甲磺酸多沙唑嗪片的人体药动学研究[J].中国医院药学杂志, 2006, 26(8):940-942.
[10]吕伟伟,孙成春,孙军,等.甲磺酸多沙唑嗪片在健康人体内的生物等效性研究[J].中国药房, 2009, 20(32):2514-2516.
[11]国家药典委员会.生物样品定量分析方法验证指导原则(中华人民共和国药典二部2015年版)[M].北京:化学工业出版社, 2015.
[12]师健鑫,卢骏,冯岩,等.甲磺酸多沙唑嗪单层渗透泵控释片的研制及Beagle犬体内的药动学[J].中国医药工业杂质, 2011, 42(5):347-350.