液质联用快速测定血浆中非布司他浓度及其人体药动学研究

 目的 研究非布司他片在中国健康受试者体内单次及多次给药的药动学特征。方法 30名受试者随机分为3组,每组10人,男女各半,一组进行非布司他片中剂量(80 mg)的单/多次给药人体药动学试验,10名受试者每天服药1次,每次80 mg,一共服药6次;一组进行非布司他片低剂量(40 mg)的单次给药人体药动学试验;一组进行非布司他片高剂量(120 mg)的单次给药人体药动学试验。血药浓度用LC-MS/MS快速测定。结果 单次空腹口服非布司他片40,80,120 mg后,其主要药动学参数如下:ρ_max分别为(2 578±743),(4 522±1 376)和(6 407±2 463) ng·mL^-1;t_max分别为(1.80±1.15),(1.78±1.18)和(2.28±1.57) h;t_1/2分别为(6.21±2.11),(6.14±0.99)和(5.93±1.82) h;AUC_{0-36 h}分别为(6 949±1 947),(14 875±4 200)和(23 881±6 225) ng·h·mL^-1;AUC_0-∞分别为(7 039±1 931),(14 995±4 287)和 (24 056±6 236) ng·h·mL^-1。多次口服80 mg非布司他片后,其主要药动学参数如下:t_max为(1.60±0.74) h,t_1/2为(5.27±1.08) h,c^SS_max为(4 326±1 477) ng·mL^-1,c^SS_min为(33.97±7.84) ng·mL^-1,c^SS_av为(622.7±165.8) ng·mL^-1,AUC^SS为(14 945±3 979) ng·h·mL^-1,AUC_{0-36 h}为(15 196±4 119) ng·h·mL^-1,AUC_0-∞为(15 291±4 110) ng·h·mL^-1。结论 非布司他片在剂量为40~120 mg内呈线性药代动力学特征,多次口服非布司他片每日1次,每次80 mg,不存在蓄积现象。

Rapid Determination of Febuxostat in Human Plasma by LC-MS/MS and Its Application to Pharmacokinetics Study

OBJECTIVE To study the pharmacokinetics of single dose and multiple doses of febuxostat tablets in Chinese healthy volunteers. METHODS Thirty healthy subjects were divided into three groups (each group consisting 5 males and 5 females) by randomized blind design. These three groups were administered single dose of 40, 80 and 120 mg febuxostat tablet respectively for single dose pharmacokinetics profile.Then the subjects of 80 mg dose group in single dose pharmacokinetics study were enrolled for a multiple-dose pharmacokinetics profile.Ten volunteers were received febuxostat tablet at 80 mg per day for 6 days. Febuxostat concentration in plasma was determined by LC-MS/MS. RESULTS After single dose oral administration, the main pharmacokinetic parameters found for febuxostat at doses of 40, 80 and 120 mg were as follows: ρ_max were (2 578±743), (4 522±1 376) and (6 407±2 463) ng·mL^-1;t_max were (1.80±1.15), (1.78±1.18) and (2.28±1.57) h; t_1/2 were (6.21±2.11), (6.14±0.99) and (5.93±1.82) h; AUC_{0-36 h} were (6 949±1 947), (14 875±4 200) and (23 881±6 225) ng·h·mL^-1; AUC_0-∞ were (7 039±1 931), (14 995±4 287) and (24 056±6 236) ng·h·mL^-1, respectively. The main pharmacokinetic parameters found for febuxostat at doses of 80 mg per day for 6 d were as follows: t_max were (1.60±0.74) h, t_1/2 were(5.27±1.08) h, c^SS_max were(4 326±1 477) ng·mL^-1, c^SS_min were (33.97±7.84) ng·mL^-1, c^SS_av were (622.7±165.8) ng·mL^-1, AUC^SS were (14 945±3 979) ng·h·mL^-1, AUC_{0-36 h} were (15 196±4 119) ng·h·mL^-1, AUC_0-∞were (15 291±4 110) ng·h·mL^-1. CONCLUSION Febuxostat tablet exhibited linear pharmacokinetics in human at doses from 40 to 120 mg after single-dose oral administration. This study confirmed that no accumulation was found after administration of multiple doses.