三氟柳胶囊单剂量与多剂量人体药动学研究

Pharmacokinetic Study on Single Dose and Multiple Dose of Triflusal Capsule in Healthy Volunteers

目的：研究三氟柳胶囊在健康人体内的药动学特征。方法：采用单中心随机试验设计,将36名健康受试者分为3组,分别单剂量口服三氟柳胶囊低、中、高剂量（300、600、900 mg）,qd,给药当天进行单剂量人体药动学研究;中剂量组继续给药13 d,进行多剂量人体药动学研究。采用液相色谱-串联质谱（LC-MS/MS）法测定三氟柳血药浓度,色谱柱为Zorbax SB-C18,流动相为甲醇-0.2%甲酸水溶液（80∶20,V/V）,流速为0.2 ml/min;采用电喷雾离子源（ESI）,以多反应监测（MRM）模式扫描,负离子方式检测,用于定量分析的离子对分别为m/z 247.1→161.1（三氟柳）、m/z 294.0→250.0（内标,双氯芬酸钠）。采用Win Nonlin 6.2软件计算药动学参数,并比较其差异。结果：三氟柳血药浓度在0.05-20.0μg/ml范围内线性关系良好。单剂量低、中、高剂量组t1/2分别为（0.45±0.20）、（0.47±0.10）、（0.43±0.20）h,tmax分别为（0.56±0.20）、（0.60±0.20）、（0.47±0.40）h,cmax分别为（3.30±0.98）、（10.65±3.26）、（13.96±4.88）μg/ml,AUC0-8 h分别为（3.99±0.93）、（13.29±1.72）、（19.62±6.78）μg·h/ml,300-900 mg剂量范围内,cmax、AUC0-8 h与剂量呈线性关系（R2分别为0.954、0.986）。多剂量给药达稳态时,平均血药浓度为（0.71±0.20）μg/ml,AUCss为（17.10±4.82）μg·h/ml,t1/2为（0.49±0.10）h,tmax为（0.85±0.62）h,cmax为（11.58±3.99）μg/ml,AUC0-8 h为（16.99±4.84）μg·h/ml,AUC0-∞为（17.08±4.81）μg·h/ml,蓄积因子为（1.28±0.40）。单剂量给药与多剂量给药的tmax和t1/2相近。结论：LC-MS/MS法能快速、准确地测定三氟柳在人体血浆中的浓度。三氟柳胶囊在健康受试者体内存在蓄积现象,且具线性药动学特征。

OBJECTIVE：To study the pharmacokinetic characteristics of triflusal capsule in healthy volunteers. METHODS：In randomized test,36 healthy volunteers were randomly divided into 3 groups. They were given low-dose,medium-dose and high-dose of Triflusal capsule（300 mg,600 mg and 900 mg）,qd,for one day,and then pharmacokinetic study of single dose of Triflusal capsule was conducted;Triflusal capsule medium-dose group was continuously given medicine for 13 days,and then pharmacokinetic study of multiple dose of Triflusal capsule was conducted. The plasma concentration of triflusal was determined by LC-MS/MS,and Zorbax SB-C18 column was used with methanol-0.2% formic acid（80 ∶ 20,V/V） at the flow rate of 0.2 ml/min. ESI was adopted in MRM mode,negative ion detection was carried out,quantitative analysis m/z 247.1→161.1（triflusal）,m/z 294.0→250.0（internal standard,diclofenac sodium）. Pharmacokinetic parameters were calculated by using Win Nonlin 6.2 software,and the difference of them were compared. RESULTS：The linear range of triflusal were 0.05-20 μg/ml. The main pharmacokinetic parameters of triflusal capsules high-dose,medium-dose and low-dose groups were as follows：t1/2were（0.45 ± 0.20）,（0.47 ± 0.10）,（0.43 ± 0.20） h;tmaxwere（0.56±0.20）,（0.60±0.20）,（0.47±0.40）h;cmax were（3.30±0.98）,（10.65±3.26）,（13.96±4.88）μg/ml;AUC0-8 hwere（3.99±0.93）,（13.29±1.72）,（19.62±6.78）μg·h/ml;within dose of 300-900 mg,linear relationship was found between cmax,AUC0-8 hand dose（R2=0.954,0.986）. When reaching stable state of multiple dose,average blood concentration was（0.71±0.20）μg/ml;main pharmacokinetic parameters were as follows：AUCss（17.10±4.82）μg·h/ml,t1/2（0.49±0.10）h,tmax（0.85±0.62）h,cmax（11.58±3.99）μg/ml,AUC0-8 h（16.99±4.84）μg·h/ml,AUC0-∞（17.08±4.81）μg·h/ml;accumulation factor（1.28±0.40）. tmaxand t1/2of single dose were similar to those of multiple dose. CONCLUSIONS：LC-MS/MS can determine the content of triflusal in human plasma rapidly and accurately,and accumulation phenomena exist in healthy Chinese volunteers,which shows linear pharmacokinetic characteristics.