三氟柳胶囊单剂量与多剂量人体药动学研究
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篇名: 三氟柳胶囊单剂量与多剂量人体药动学研究
TITLE:
摘要:

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WinNonlin 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0.05~20.0 μg/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。

ABSTRACT:

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 WinNonlin 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:t1/2 were(0.45 ± 0.20),(0.47 ± 0.10),(0.43 ± 0.20)h;tmax were

(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 h were(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 h and 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). tmax and t1/2 of 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.

 

期刊: 2015年第26卷第35期
作者: 彭莉,丁莉坤,贾艳艳,王茂湖,文爱东
AUTHORS: PENG Li,DING Li-kun,JIA Yan-yan,WANG Mao-hu,WEN Ai-dong
关键字: 三氟柳;剂量;液相色谱-串联质谱法;血药浓度;药动学
KEYWORDS: Triflusal;Dose;LC-MS/MS;Plasma concentration;Pharmacokinetics
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