雷诺嗪缓释片在中国健康人体内的药代动力学研究

Pharmacokinetic study of ranolazine in Chinese healthy volunteers

目的评价雷诺嗪缓释片单次和多次口服给药后在中国健康人体内的药代动力学特征。方法采用自身对照试验设计,单次、多次给药组各纳入10例健康受试者,男女各半,单次分3个周期依次服用500、1 000、1 500 mg雷诺嗪缓释片;多次分2个周期依次服用500、1 000 mg雷诺嗪缓释片;采用高效液相色谱-串联质谱(LC-MS-MS)法测定血浆样品中雷诺嗪的浓度,计算主要药代动力学参数。结果血浆中雷诺嗪浓度线性范围为40～4 000μg/L,定量下限为40μg/L,批内、批间精密度均小于15%。单次给药3个不同剂量(500、1 000、1 500 mg)的Cmax分别为(774±157)、(1 818±554)、(2 762±1 099)μg/L;tmax分别为(4.9±1.8)、(4.9±2.6)、(4.9±1.5) h;t1/2z分别为(8.2±6.8)、(10.3±8.7)、(9.7±12.0) h;AUC0-t分别为(8 470±2 765)、(20 936±6 957)、(32 554±17 780)μg·h/L。多次给药2个不同剂量(500、1 000 mg) Cmaxss分别为(1 826±904)、(3 635±620)μg/L;Cminss分别为(1 022±3)、(2 282±163)μg/L;Cav分别为(1 253±634)、(2 615±536)μg/L;AUC0-t分别为(22 452±12 359)、(53 232±15 909)μg·h/L;MRT0-t分别为(8.7±2.3)、(10.6±2.6);RAUC分别为(3.11±2.60)、(2.86±1.54)。结论在单次给药试验中Cmax和AUC与剂量呈比例增加,且3个给药剂量有很好的线性关系;多次给药试验发现雷诺嗪在健康人体内有一定的积累。

Objective To evaluate pharmacokinetics after administration of ranolazine sustained release tablets at a single and multiple dose to healthy Chinese volunteers.Methods A self-controlled trial design was used.In the single-time group,10 healthy volunteers,half male and half female,were included,and 500,1 000 and 1 500 mg ranolazine sustained-release tablets were taken sequentially in 3 cycles.For the multiple-dose group,10 individuals of both sexes were enrolled,and 500 and 1 000 mg ranolazine sustainedrelease tablets were sequentially administered in 2 cycles.The concentration of ranolazine in plasma samples was determined by LC-MS-MS,and the main pharmacokinetic parameters were calculated.Results The linear concentration of ranolazine in plasma ranged from 40 to 4 000 μg/L,and the LLOQ was 40 μg/L.The intra-assay and inter-assay precision were less than 15%.After single dose,the main parameters in doses500,1 000,1 500 mg were Cmax:774±157,1 818±554 and 2 762±1 099 μg/L,respectively;tmax:4.9±1.8,4.9±2.6 and 4.9±1.5 h,respectively;t1/2z:8.2±6.8,10.3±8.7 and 9.7±12.0 h,respectively;AUC0-t:8 470±2 765,20 936±6 957 and 32 554±17 780 μg·h/L,respectively.After multiple dose,the main parameters in doses 500,1 000 mg were Cmaxss:1 826±904 and 3 635±620 μg/L;Cminss:1 022±3 and 2 282±163 μg/L;Cav:1 253±634 and 2 615±536 μg/L;AUC0-t:22 452±12 359 and 53 232±15 909 μg·h/L;MRT0-t:8.7±2.3 and 10.6±2.6;RAUC:3.11±2.60 and 2.86±1.54.Conclusion In a single administration trial,Cmaxand AUC are increased proportionally to the dose,and there is a good linear relationship between the three doses.Multiple dose tests have found that ranolazine has a certain accumulation in the body.