非布司他在中国健康人体内药动学和药效学

Pharmacokinetics and pharmacodynamics of febuxostat under fasting conditions in healthy Chinese subjects

目的:研究国产非布司他在中国健康受试者体内药动学和药效学特点。方法:36名健康受试者随机分组,分别接受单剂量空腹口服非布司他片40,80,120 mg和多剂量空腹口服非布司他片80 mg,给药前后不同时间取血测定血药浓度、血清尿酸水平(UA)。采用HPLC-MS-MS法测定受试者血浆样品中非布司他的浓度。UA为临床检验所得。结果:(1)非布司他在40～120 mg剂量范围内,呈线性药动学特征;连续给药在健康受试者体内不存在蓄积。(2)单次空腹口服40,80,120 mg非布司他后,结果表明给药剂量与UA24呈线性特征;对3个剂量组UA24/Dose进行方差分析,表明各剂量组间有显著性差异(P<0.05)。(3)连续给药(80 mg,qd×7 d)后第3天UA下降了38.13%,第7天下降达52.69%,第4～7天稳定在低值状态(145.2±10.3)(mol·L-1,与给药前1天基础值(UA-1)相比,连续给药7 d平均降低(51.8±7.0)%。结论:健康受试者空腹口服国产非布司他片,以UA为临床药效指标,通过降低血尿酸水平而呈现出药理活性。单次给药在40,80和120 mg组间UA降低显示明显的剂量依赖性。连续给药3 d即可产生显著的降尿酸作用,给药7 d平均降低(51.8±7.0)%。健康受试者UA在停药后48 h恢复至正常值范围。

OBJECTIVE To study the pharmacokinetic and pharmacodynamic characteristics of domestic febuxostat after single oral dose and multiple oral doses under fasting conditions in healthy Chinese subjects.METHODS Thirty-six healthy subjects were randomized to receive febuxostat by single oral dose（40,80,120 mg）and multiple oral doses（80 mg,qd×7 d）under fasting conditions.At a series of time points before or after administration,the blood samples were collected,the plasma drug levels and serum uric acid（UA） were determined by HPLC-MS-MS mothod and clinical laboratory test,respectively.RESULTS During the dosage of 40-120 mg of febuxostat it showed a linear pharmacokinetic character.Drug accumulation was not detected after multiple oral doses.When febuxostat was administered at a single dose of 40 mg,80 mg and120 mg,UA24 was linearly corrected to the dosage.The relationship between effect UA24 and the three single doses（40,80 mg and120 mg）was analzed with ANOVA.The difference between every single dose was significant（P0.05）.After three day,the percentage decrease in serum uric acid（UA0-24h）was 38.13%.After seven day,the percentage decrease in serum uric acid（UA0-24h）was 52.69%.Mean percentage decrease was 51.83%±7.0% within seven days.CONCLUSION Domestic febuxostat can be decrease the level of serum uric acid,and the decrease of UA is linear corresponding to dosage.Mean percentage decrease was 51.83%±7.0% within seven days.The clinic indexes of UA returned to normal range after drug discontinuance in healthy subjects.