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目的评价中国健康受试者口服雷诺嗪缓释片后的药动学参数。方法本次试验为双盲、随机试验。所有受试者根据入组先后依次分配至7个剂量组,其中,6个剂量组为单次给药,分别给予500、1 000、1 500、2 000、2 500、3 000 mg雷诺嗪缓释片;1个剂量组多次给予500 mg雷诺嗪缓释片。采用LC-MS/MS测定雷诺嗪的血浆药物浓度。结果血浆中雷诺嗪浓度线性范围为5~4 000 ng·mL-1,定量下限为5 ng·mL-1,日内、日间精密度均小于15%。单次给药后,500、1 000、1 500、2 000、2 500、3 000 mg剂量组主要药动学参数如下:AUC0-t分别为(4 876±1 030),(9 135±3 796),(17 562±8 249),(14 401±6 848),(19 410±10 678),(26 170±9 896)ng·mL-1·h-1;MRT0-t分别为(10.17±1.94),(11.39±4.19),(12.35±3.87),(12.71±3.22),(8.39±3.16),(12.48±4.78)h;t1/2分别为(4.74±1.29),(5.35±2.21),(5.53±2.82),(8.64±5.22),(3.97±1.24),(11.64±6.40)h;ρmax分别为(471.78±132.84),(856.00±241.33),(1 265.01±501.10),(1 378.72±900.85),(1 980.65±802.75),(3 075.78±1 516.90)ng·mL-1;CL分别为(106.34±24.33),(145.70±121.72),(103.29±48.25),(165.28±81.50),(158.69±77.85),(110.11±31.20)L·h-1;多次给药后,第1次给药后AUC0-t为(5 593±4 592)ng·mL-1·h-1,MRT0-t为(10.23±3.22)h,t1/2为(6.39±2.84)h,ρmax为(527.42±340.15)ng·mL-1;CL为(155.19±133.14)L·h-1;受试者第10次给药后,AUC0-t为(12 318±7 353)ng·mL-1·h-1;MRT0-∞为(11.56±2.14)h,t1/2为(5.11±1.19)h,ρmax为(1 007.78±455.95)ng·mL-1,ρmin为(357.03±268.34)ng·mL-1,ρavg为(654.29±341.59)ng·mL-1,CLss为(82.89±50.42)L·h-1,Flu为(109.04±29.93)%,Accumulation为(1.25±0.12),经比较雷诺嗪在体内无蓄积。结论本试验探讨了雷诺嗪缓释片在中国健康受试者体内药动学特征,并和文献数据进行比较,结果显示,单次及多次给药后雷诺嗪缓释片药动学参数与文献的数据基本一致。
Objective To evaluate the pharmacokinetic parameters of ranolazine sustained-release tablets in healthy Chinese subjects. Methods This trial was a double-blind, randomized trial. All subjects were assigned to 7 dose groups according to the enrollment group, of which 6 dose groups were given as a single dose and given 500, 1000, 1 500, 2 000, 2 500, 3 000 mg ranolazine respectively Release tablets; 1 dose group was given 500 mg ranolazine sustained-release tablets. Plasma concentrations of ranolazine were determined by LC-MS / MS. Results The plasma concentration of ranolazine ranged from 5 to 4 000 ng · mL-1 with a lower limit of quantitation of 5 ng · mL-1. The intra- and inter-day precision was less than 15%. The main pharmacokinetic parameters of the 500,1 000,1 500,2 000,2 500,3 000 mg dose groups after single administration were as follows: AUC0-t were (4876 ± 1 030), (9135 ± 3) 796, 17 562 ± 8 249, 14 401 ± 6 848, 19 410 ± 10 678, 26 170 ± 9 896 ng · mL-1 · h-1, respectively; MRT0-t were 10.17 ± 1.94), (11.39 ± 4.19), (12.35 ± 3.87), (12.71 ± 3.22), (8.39 ± 3.16) and (12.48 ± 4.78) h respectively, and t1 / 2 were 4.74 ± 1.29 and 5.35 ± 2.21, 5.53 ± 2.82, 8.64 ± 5.22, 3.97 ± 1.24, 11.64 ± 6.40 h respectively; ρmax were (471.78 ± 132.84), (856.00 ± 241.33), (1265.01 ± 501.10), (1 378.72 ± 900.85), (1 980.65 ± 802.75), (3 075.78 ± 1 516.90) ng · mL-1, respectively; CL were 106.34 ± 24.33, 145.70 ± 121.72, 103.29 ± 48.25, 165.28 ± 81.50), (158.69 ± 77.85) and (110.11 ± 31.20) L · h-1, respectively. After multiple administrations, the AUC0-t after the first administration was (5993 ± 4 592) ng · mL- (10.23 ± 3.22) h, t1 / 2 was (6.39 ± 2.84) h, ρmax was (527.42 ± 340.15) ng · mL-1, and CL was (155.19 ± 133.14) L · h- 1; the AUC0-t was (12 318 ± 7 353) ng · mL-1 · h-1 after the 10th dose of the test substance; the MRT0-∞ was (11.56 ± 2.14) ± 1.19) h, ρmax was (1007.78 ± 455.95) ng · mL-1, ρmin was (357.03 268.34 ng · mL -1, ρavg was (654.29 ± 341.59) ng · mL -1, CLss was (82.89 ± 50.42) L · h -1, Flu was (109.04 ± 29.93)% and Accumulation was (1.25 ± 0.12) , Compared with ranolazine in the body without accumulation. Conclusion This study explored the pharmacokinetics of ranolazine sustained-release tablets in healthy Chinese subjects, and compared with the literature data, the results show that single and multiple doses of ranolazine sustained-release tablets pharmacokinetic parameters and The literature data are basically the same.