中国健康志愿者连续口服D-聚甘酯片药动学研究

 目的研究中国健康成年男性志愿者连续口服D-聚甘酯片的药动学。方法选择经体检及实验室检查均正常的健康成年男性志愿者。12名受试者连续口服D-聚甘酯片10 d，每日一次，每次400 mg。应用免疫荧光比浊法测定给药后不同时间点血浆的部分凝血活酶时间(aPTT)，据随行测定的aPTT-血浆浓度标准曲线，计算相应的血药浓度。采用3P97软件进行数据处理，分别求出首次给药和末次给药后药动学参数，以及达稳态时间、稳态浓度、累积比和波动系数。结果依据aPTT结果计算D-聚甘酯血浆浓度，在0.05～10mg·L^-1浓度范围内呈良好的线性关系(r=0.995 7)；最低检测浓度为0.05 mg·L^-1，回收率在91.48%～105.67%之间，日内、日间RSD小于13%。受试者连续口服D-聚甘酯片，于给药后第7天血药浓度达到稳态，平均稳态血药浓度c_av为(0.442±0.067) mg·L^-1，达稳态后血药浓度时间曲线下面积AUC_ss为(10.602±1.605) mg·h·L^-1，累积比R为1.261±0.031，波动系数FI为1.554±0.061。首次与末次给药后主要药动学参数c_max分别为(1.041±0.107)和(1.401±0.125) mg·L^-1；t_1/2β-分别为(18.934±1.760)和(19.977±1.098) h；t_max分别为(1.039±0.096)和(0.969±0.109)h；V/F分别为(202.167±19.187)和(160.220±22.274) L；CL分别为(33.553±5.038)和(24.807±3.875) L·h^-1。首次给药后AUC_0～∞为(12.195±1.912) mg·h·L^-1，末次给药后AUC_0～τ为(10.602±1.605) mg·h·L^-1。结论健康受试者连续口服D-聚甘酯片后第7天血药浓度达到稳态，连续口服D-聚甘酯片10 d，体内无蓄积。受试者服药期间除发生aPTT延长正常的药理效应外，未发现其它与药物有关的不良事件。每日1次给药方案是合理可行的。

Pharmacokinetics of multi-dose D-polymannuronicate tablets in Chinese healthy volunteers

OBJECTIVE To investigate the pharmacokinetics of D-polymannuronicate after multiple dose administration in Chinese healthy volunteers. METHODS 11 volunteers passed physical and laboratory examinations took orallyD-polymannuronicate 400 mg once daily for 10 days.The aPTT was determined by immuno fluoresence turbidity method and the plasma concentrations of D-polymannuronicate were determined by the accompanily aPTT.The plasma concentration standard curve and pharmacokinetic parameters of the first and the last dosing were calculated by 3P97 software. RESULTS The steady concentrations were achieved after administration for 7 days.The mean steady plasma concentration (c_av) was (0.442±0.067) mg·L^-1.The AUC_ss,accumulation rate R and the fluctation coefficient FI were (10.602±1.605) mg·h·L^-1,(1.261±0.031),(1.554±0.061) respectively.The main parameters after the first and the last dosing were as follow:c_max(1.041±0.107) and (1.401±0.125) mg·L^-1,t_1/2β(18.934±1.760) and (19.977±1.098) h,t_max(1.039±0.096) and (0.969±0.109) h,V/F (202.167±19.187) and (160.220±22.274) L,CL(33.553±5.038) and (24.807±3.875) L·h^-1 respectively.The AUC_0～∞after the first dosing was (12.195±1.912) mg·h·L^-1and the AUC_0～tafter the last dosing was (10.602±1.605) mg·h·L^-1. CONCLUSION The steady concentration was achieved after administration for 7 days and there was no accumulation in vivo for 10 days.No correlated adverse effects took place except aPTT elongation.Once daily administration of D polymannuronicate was recommended.