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目的:研究口服奈必洛尔在中国健康志愿者中的单次及连续多次给药药动学特征。方法:16名健康受试者采用随机、开放、2×2交叉试验设计,单次给药剂量为5、10 mg;多次给药为每天5 mg,连续7 d。给药后于不同时间点采集肘静脉血,采用LC-MS/MS法测定奈必洛尔血药浓度,药动学参数采用Win Nonlin软件计算。结果:单次口服5 mg盐酸奈必洛尔片后奈必洛尔的主要药动学参数:t1/2为(11.1±5.6)h;AUClast为(9.3±7.7)μg·h·L-1;AUCinf为(8.2±7.2)μg·h·L-1;Cmax为(1.3±0.7)μg/L;CL/F为(1.9±1.5)L/h;MRT为(12.3±5.5)h。单次口服10 mg盐酸奈必洛尔片后奈必洛尔的主要药动学参数:t1/2为(11.1±5.7)h;AUClast为(20.0±17.3)μg·h·L-1;AUCinf为(18.3±16.2)μg·h·L-1;Cmax为(2.4±1.2)μg/L;CL/F为(2.0±1.7)L/h;MRT为(13.4±6.9)h。多次给药主要药动学参数:t1/2为(8.3±3.2)h;AUClast为(15.7±12.8)μg·h·L-1;AUCinf为(14.7±12.7)μg·h·L-1;Cmax为(2.4±1.2)μg/L;CL/F为(0.6±0.3)L/h;MRT为(9.3±3.4)h。单次给药的AUC值显著低于多次给药。结论:奈必洛尔体内药动学在5 mg和10 mg剂量范围内呈现出比例化剂量反应关系的趋势。按每天5 mg给药7 d,奈必洛尔血药浓度可达稳态,体内呈现明显的蓄积趋势。
OBJECTIVE: To study the pharmacokinetics of oral nebivolol in single and continuous multiple administrations in Chinese healthy volunteers. Methods: Sixteen healthy subjects were randomized, open and 2 × 2 crossover design. The single dose was 5 and 10 mg. The multiple doses were 5 mg daily for 7 days. Elbow vein blood was collected at different time points after administration, and plasma concentration of nebivolol was determined by LC-MS / MS. The pharmacokinetic parameters were calculated by Win Nonlin software. Results: The main pharmacokinetic parameters of nebivolol after 5 mg single dose of nebivolol hydrochloride tablet were: t1 / 2 (11.1 ± 5.6) h and AUClast (9.3 ± 7.7) μg · h · L-1 ; AUCinf was (8.2 ± 7.2) μg · h · L-1; Cmax was (1.3 ± 0.7) μg / L; CL / F was (1.9 ± 1.5) L / h and MRT was (12.3 ± 5.5) h. The main pharmacokinetic parameters of nebivolol after a single oral administration of 10 mg nebivolol hydrochloride tablets were: t1 / 2 (11.1 ± 5.7) h, AUClast (20.0 ± 17.3) μg · h · L-1; AUCinf (18.3 ± 16.2) μg · h · L-1; Cmax was (2.4 ± 1.2) μg / L; CL / F was (2.0 ± 1.7) L / h and MRT was (13.4 ± 6.9) h. The main pharmacokinetic parameters of multiple administrations were: t1 / 2 (8.3 ± 3.2) h, AUClast (15.7 ± 12.8) μg · h · L-1 and AUCinf was (14.7 ± 12.7) μg · h · L-1 ; Cmax was (2.4 ± 1.2) μg / L; CL / F was (0.6 ± 0.3) L / h; MRT was (9.3 ± 3.4) h. AUC values for single administration were significantly lower than those for multiple administrations. Conclusion: The pharmacokinetics of nebivolol showed a trend of proportional dose response in the range of 5 mg and 10 mg doses. By daily administration of 5 mg 7 d, nebivolol plasma concentration reached steady state, the body showed a significant accumulation trend.