复方单硝酸异山梨酯缓释片的人体药动学和生物等效性研究

 目的研究复方单硝酸异山梨酯缓释片的人体药动学和生物等效性。方法健康受试者交叉口服单剂量和多剂量受试制剂和参比制剂,用高效液相色谱质谱检测器(MSD)和二极管阵列检测器(DAD)串联在线测定血浆中单硝酸异山梨酯和水杨酸的浓度;单硝酸异山梨酯用高效液相色谱电喷雾质谱(HPLC/ESIMS)选择离子检测,水杨酸用DAD检测。结果单剂量口服受试制剂和参比制剂后,单硝酸异山梨酯的AUC_0→36h分别为(100251±13369)和(94720±11393)μg·h·L^-1,t_max分别为(47±10)和(45±08)h,c_max分别为(6619±765)和(6580±832)μg·L^-1;水杨酸的AUC_0→∞分别为(21864±6329)和(18872±5379)μg·h·L^-1,t_max分别为(08±04)和(47±10)h,c_max分别为(6050±1133)和(3797±872)μg·L^-1。受试制剂单硝酸异山梨酯和水杨酸的相对生物利用度分别为(1059±64)%和(1175±193)%。受试者口服多剂量受试制剂和参比制剂后,单硝酸异山梨酯的AUC^ss_0→24h分别为(103335±15192)和(104105±17675)μg·h·L^-1,t_max分别为(43±11)和(43±08)h,c_max分别为(7248±955)和(7867±1100)μg·L^-1,c_min分别为(1294±400)和(1219±360)μg·L^-1,c_av分别为(4306±633)和(4338±736)μg·L^-1,DF分别为(1401±159)%和(1552±207)%;稳态时受试制剂单硝酸异山梨酯的相对生物利用度为(100.5±13.0)%。结论 以单硝酸异山梨酯为研究对象,受试制剂与参比制剂具有生物等效性;以阿司匹林为研究对象，受试制剂和参比制剂吸收程度相当,吸收速度较快。

Study on the pharmacokinetics and bioequivalence of isosorbide 5-mononitrate and aspirin from compound isosorbide mononitrate sustained release tablets in healthy volunteers

OBJECTIVE To study the pharmacokinetics and bioequivalence of isosorbide 5-mononitrate and aspirin from compound isosorbide mononitrate sustained released tablets in healthy volunteers.METHODS Isosorbide mononitrate sustained release tablets and aspirin enteric-coated tablets were used as the reference preparations.In a randomized crossover design,single and multiple doses of test and reference preparations were given to 20 and 18 healthy male volunteers respectively. Isosorbide-5-mononitrate and salicylic acid concentrations were measured by ESI-MSD and DAD respectively. RESULTS After a single oral administration,the pharmacokinetic parameters of isosorbide 5-mononitrate test and control preparations were as following:AUC_0→36h (10 025.1±1 336.9) and (9 472.0±1 139.3)μg·h·L^-1 ;t_max (4.7±1.0) and (4.5±0.8) h;c_max (661.9±76.5) and (658.0±83.2) μg·L^-1, respectively. For salicylic acid, the pharmacokinetic parameters were as AUC_0→∞(21 864±6 239) and (18 872±5 379) μg·h·L^-1 ;t_max (0.8±0.4) and (4.7±1.0) h;c_max (6 050±1 133) and (3 797±872)μg·L^-1 ,respectively. The relative bioavailability of isosorbide 5-mononitratte and salicylic acid were (105.9±6.4)% and (117.5±19.3)%,respectively. After multiple oral administration of test and reference preparations,the pharmacokinetic parameters were as following:AUC_ss(10 333.5±1 519.2) and (10 410.5±1 767.5) μg·h·L^-1 ;t_max (4.3±1.1) and (4.3±0.8) h;c_max (724.8±95.5) and (786.7±110.0) μg·L^-1 ;c_min (129.4±40.0) and (121.9±36.0) μg·L^-1 ;c_av (430.6±63.3) and (433.8±73.6) μg·L^-1; DF(140.1±15.9)% and (155.2±20.7)%,respectively. The relative bioavailability of isosorbide 5-mononitrate was (100.5±13.0)%. CONCLUSION Compoud isosorbide mononitrate sustained release tablets showed bioequivalence for the isosorbide 5-mononitrate component with the reference preparation, and the AUC for the aspirin component was bioequivalent with that of the reference drug,but the test drug was more rapidly absorbed.