高效液相-荧光法测定人血浆中非布司他的浓度及其人体药动学研究

Determination of the contents of febuxostat in human plasma by HPLC-FLU and studies on its pharmacokinetics

目的:建立测定人血浆中非布司他浓度的方法,研究非布司他片的药代动力学。方法:12名健康受试者采用3×3简化拉丁方设计,分别于不同周期服用40、80、120mg非布司他片进行单剂量药动学研究,按80mg剂量连续给药7d(每天一次)进行多剂量药动学研究。血样经含10%乙酸的乙腈萃取,采用高效液相-荧光法(HPLC-FLU)检测。以甲醇∶0.1%甲酸水溶液(71∶29,V/V,梯度:0～5.2min=71∶29,7～10min=90∶10,10.2～12.5min=71∶29)为流动相,流速:1mL/min。荧光检测器激发波长320nm,发射波长380nm。内标为2-萘甲酸。结果:该法在0.025～10mg/L浓度范围内呈线性关系,r=0.9996。最低检测浓度0.005mg/L,平均提取回收率为94.3%,日内RSD 1.53%、日间RSD2.27%。12名健康受试者单剂量口服非布司他40、80、120mg的主要药动学参数为Cmax=(1.63±0.54)、(3.59±1.23)、(4.76±1.15)mg/L,tmax=(1.29±0.60)、(1.06±0.68)、(1.71±0.98)h,AUClast=(4.94±1.21)、(11.68±2.80)、(18.93±5.27)mg.h.L-1;多剂量口服非布司他80mg Cmax=(4.19±1.44)mg/L,tmax=(1.31±0.97)h,AUCss=(12.42±3.31)mg.h.L-1。结论:口服非布司他片在健康人体内的药动学符合一级线性药代动力学特征,多次给药体内无蓄积作用。非布司他片在中国健康人体内的药动学行为与国外文献报道基本一致。

AIM：To study the pharmacokinetics of febuxostat tablets and establish an HPLC method for determining the contents of the febuxostat in human plasma. METHODS：12 healthy volunteers were used 3×3 simplified Latin square design.The volunteers divided into 3 groups were administrated with single dose febuxostat 40,80,120 mg respectively,then 80 mg a day for seven days.The plasma concentration of the drug were determined by HPLC-FLU method.Methanol：the mobile phase was 0.1% formic acid（gradient,V/V：0-5.2 min = 71∶29,7-10 min = 90∶10,10.2-12.5 min = 71∶29）.The flow rate was 1.0 mL/min.The excitation wavelength and emission wavelength were 320 nm and 380 nm,respectively.Internal standard was 2-carboxylic acid. RESULTS：The linear ranges of febuxostat was 0.025-10 mg/L（r=0.9996）,the detection limit was 0.005 mg/L,the average recovery was 94.3%,both the RSD for intra-day and inter-day were 1.53%,2.27%.Among 12 healthy subjects,the main pharmacokinetic parameters of febuxostat in single dose of 40、80、120 mg were as follows：Cmax=（1.63±0.54）,（3.59±1.23）,（4.76±1.15） mg/L,tmax=（1.29±0.60）,（1.06±0.68）,（1.71±0.98） h,AUClast=（4.94±1.21）,（11.68 ±2.80）,（18.93±5.27） mg·h·L-1;The pharmacokinetic parameters of multi-dose administration（80 mg） were Cmax=（4.19±1.44） mg/L,tmax=（1.31±0.97） h,AUCss=（12.42±3.31） mg·h·L-1. CONCLUSION：After administration of multi-dose febuxostat,no accumulation occurs in vivo.The pharmacokinetic characteristics of febuxostat tablets were consistent with foreign reports.