中国临床药学杂志

目的建立用于测定人血浆中复方替米沙坦片中两种成分替米沙坦和氢氯噻嗪的HPLC测定方法,并用于研究健康志愿者口服复方替米沙坦片的药动学特征。方法 12名健康志愿者口服试验片剂,于规定时间点取血,分别用高效液相-荧光法和高效液相-二级质谱联用测定人血浆中替米沙坦和氢氯噻嗪浓度。用梯形法计算AUC,以实测值计算t_max和ρ_max,采用药动学统计软件DAS2.0计算其他药动学参数。结果替米沙坦的线性范围为2.5～500μg·L^-1,r=0.999 9,方法回收率99.42%～108.69%,RSD均≤2.62%,最低检测浓度为1.25μg·L^-1;氢氯噻嗪的线性范围为1～200μg·L^-1(r=0.999 4),方法回收率95.58%～112.15%,RSD均≤4.86%,最低检测浓度为0.5μg·L^-1。12名受试者口服复方替米沙坦后,替米沙坦的主要药动学参数为:AUC_0→t(1 800±859)μg·h·L^-1,AUC_0→∞(1 967±858)μg·h·L^-1,ρ_max(181±68)μg·L^-1,t_max(1.7±0.9)h,t_1/2(22.15±10.64)h。氢氯噻嗪的主要药动学参数为AUC_0→t(519±151)μg·h·L^-1,AUC_0→∞(542±149)μg·h·L^-1,ρ_max(72.3±25.1)μg·L^-1,t_max(2.3±0.9)h,t_1/2(7.44±2.50)h。结论建立的替米沙坦和氢氯噻嗪的HPLC测定方法灵敏、准确、专属,适合于复方制剂两成分的血药浓度测定。体内药动学研究表明该复方制剂两成分没有改变各自体内的药动学行为。

AIM To develop high performance liquid chromatography(HPLC) methods for the determination of telmisartan and hydrochlorothiazide in human plasma,which were utilized to study the pharmacokinetics of telmisartan compound tablet in 12 healthy male volunteers.METHODS A single oral dose compound tablet was given to each volunteer according to an open,single-center study.The telmisartan and hydrochlorothiazide concentrations in plasma were determined by HPLC-fluorescence and LC-MS/MS(tandem mass sepctrometry) method respectively.AUC was calculated by trapezoidal rule.The measured value of t_max andρ_max was used as the final one,and the other main pharmacokinetic parameters were caculated by program DAS 2.0.RESULTS The calibration curve of telmisartan was linear in the range of 2.5-500μg·L^-1(r=0.999 9).The detection of limit(LOD) was calculated to be 1.25μg·L^-1.The recovery of telmisartan was demonstrated to be 99.42%-108.69%,with RSD lower than 2.62%.As for hydrochlorothiazide,a good linear correlation was obtained in the range of 1-500μg·L^-1(r=0.999 4) with the LOD of 0.5μg·L^-1.And the recovery of hydrochlorothiazide was demonstrated to be 95.58%-112.15%,with RSD lower than 4.86%.The main pharmacokinetic parameters of telmisartan in 12 volunteers were as follows:AUC_0→t,was(1800±859)μg·L^-1; AUC_0→∞ was(1967±858)μg·h·L^-1;ρ_max was(181±68)μg·L^-1;t_max was(1.7±0.9) h;t_1/2 was(22.15±10.64) h.The phannacokinetic parameters of hydrochlorothiazide were as follows:AUC_0→t was(519±151)μg·h·L^-1; AUC_0→∞ was(542±149)μg·h·L^-1;ρ_max was(72.3±25.1)μg·L^-1;t_max was(2.3±0.9) h;t_1/2 was(7.44±2.50) h.CONCLUSION The established methods are sensitive,accurate,specific,and suitable for the determination of two components in human plasma after a single oral dose of compound tablet.The main pharmacokinetic parameters of telmisartan and hydrochlorothiazide have no significant differences from the data offered by the references.It is demonstrated that there is no cross-talk on drug effect in vivo between these two components.