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目的:研究中国健康受试者单次和多次口服复方替米沙坦胶囊的药代动力学特点。方法:20名健康受试者随机分为2组,分别单次口服低、高剂量复方替米沙坦胶囊(每粒含替米沙坦40mg,氢氯噻嗪12.5mg);8名健康受试者口服复方替米沙坦胶囊1粒,连续服用7d,采用LC-MS/MS方法测定血浆药物浓度,并计算药代动力学参数。结果:受试者单次口服复方替米沙坦胶囊1粒或2粒后替米沙坦的主要药代动力学参数:Cmax分别为(130.65±125.97)、(876.22±588.52)μg·L-1,tmax分别为(1.72±0.96)、(1.03±0.48)h,AUC0-t分别为(1745.22±1634.54)、(4776.26±3703.07)μg·h·L-1,AUC0-∞分别为(1882.11±1704.30)、(5060.78±3955.61)μg·h·L-1;单次口服复方替米沙坦胶囊1粒或2粒后氢氯噻嗪的主要药代动力学参数:Cmax分别为(70.62±23.05)、(120.42±51.41)μg·L-1,tmax分别为(1.95±1.01)、(2.30±1.14)h,AUC0-t分别为(498.99±162.45)、(888.83±384.29)μg·h·L-1,AUC0-∞分别为(511.32±161.02)、(910.67±390.77)μg·h·L-1。连续7d口服复方替米沙坦胶囊1粒后替米沙坦和氢氯噻嗪的主要药代动力学参数:Cmax分别为(199.27±133.79)、(53.52±11.54)μg·L-1,tmax分别为(1.33±1.14)、(2.38±1.03)h,AUCss分别为(1211.13±774.94)、(405.80±142.41)μg·h·L-1,Cav分别为(50.46±32.29)、(16.91±5.93)μg·L-1,DF分别为(3.61±1.61)、(3.18±0.59)。结论:单次口服复方替米沙坦胶囊后,替米沙坦在40,80mg时的AUC和Cmax的增加比例显著高于剂量增加比例,呈非线性药代动力学特征;氢氯噻嗪在12.5,25mg时的AUC和Cmax的增加与剂量增加成正比,呈线性药代动力学特征。连续给药与单次给药相比,其药代动力学特征未发生显著变化。
Objective: To study the pharmacokinetics of single and multiple oral compound telmisartan capsules in healthy Chinese subjects. Methods: Twenty healthy volunteers were randomly divided into two groups. Each group received low and high doses of compound telmisartan capsules (each containing telmisartan 40 mg and hydrochlorothiazide 12.5 mg). Eight healthy volunteers were orally One tablet of compound telmisartan was administrated for 7 consecutive days. The plasma drug concentration was determined by LC-MS / MS and the pharmacokinetic parameters were calculated. RESULTS: The main pharmacokinetic parameters of telmisartan in single oral administration of telmisartan capsules were 130.65 ± 125.97 and 876.22 ± 588.52 μg · L- 1, tmax were (1.72 ± 0.96) and (1.03 ± 0.48) h respectively, AUC0-t were (1745.22 ± 1634.54) and (4776.26 ± 3703.07) μg · h · L-1, (5060.78 ± 3955.61) μg · h · L-1. The main pharmacokinetic parameters of hydrochlorothiazide after a single oral administration of telmisartan capsules were as follows: Cmax were (70.62 ± 23.05), ( 120.42 ± 51.41) μg · L-1 and tmax were (1.95 ± 1.01) and (2.30 ± 1.14) h, respectively. The AUC0-t was 498.99 ± 162.45 and 888.83 ± 384.29 μg · h · L- AUC0-∞ were (511.32 ± 161.02) and (910.67 ± 390.77) μg · h · L-1, respectively. The main pharmacokinetic parameters of telmisartan and hydrochlorothiazide after oral administration of one compound telmisartan capsule for 7 days were as follows: C max were (199.27 ± 133.79) and (53.52 ± 11.54) μg · L -1 respectively, tmax was AUCss were (1211.13 ± 774.94) and (405.80 ± 142.41) μg · h · L-1, respectively, and were respectively 1.33 ± 1.14 and 2.38 ± 1.03 h. Cav was respectively (50.46 ± 32.29) and (16.91 ± 5.93) μg · L-1 and DF were (3.61 ± 1.61) and (3.18 ± 0.59) respectively. CONCLUSIONS: After a single oral administration of compound telmisartan capsules, the increase in AUC and Cmax of telmisartan at 40 and 80 mg was significantly higher than that at dose-increasing, showing a nonlinear pharmacokinetic profile. Hydrochlorothiazide at 12.5 and 25 mg The increase in AUC and Cmax was proportional to dose increase with linear pharmacokinetic characteristics. There was no significant change in pharmacokinetic characteristics of continuous administration compared to single administration.