摘要
目的:研究中国健康志愿者单剂量和多剂量口服米屈肼胶囊的耐受性和药动学。方法:健康志愿者40名,按随机区组设计,分为5组,每组男女各4名,分别单次口服米屈肼胶囊250,500,1 000,1 250mg和1 500mg,进行耐受性和单剂量药动学试验。经过1周洗脱期后,单剂量试验中500mg剂量组的受试者,进行多次给药药动学试验,8名受试者每天服药3次,每次500mg,连续服药13 d。试验期间通过观察药品不良反应,监测生命体征实验室数据的变化,评估药物的安全性和耐受性。血药浓度采用HPLC-MS法测定,以计算其主要药动学参数并进行统计学分析。结果:试验期间未发生严重不良事件。单次口服米屈肼胶囊250,500,1 000,1 250mg和1 500mg后,其主要药动学参数:tmax分别为(1.2±0.3),(1.0±0.4),(1.2±0.6),(1.2±0.4)h和(1.0±0.4)h;t1/2分别为(3.6±0.7),(5.3±1.2),(6.1±0.5),(6.1±0.4)h和(6.6±0.9)h;MRT0-24分别为(7.3±0.9),(8.4±1.1),(8.7±1.5),(8.7±0.7)h和(9.0±1.1)h;V/F分别为(39±7),(54±12),(66±9),(68±7)L和(71±14)L;CL/F分别为(7.6±1.2),(7.2±1.1),(7.5±1.1),(7.8±1.0)L.h-1和7.5±1.3L.h-1;Cmax分别为(5.9±0.9),(13.8±3.2),(30.4±6.3),(35.5±13.1)μg.mL-1和(46.3±14.1)μg.mL-1;AUC0-24分别为(32±6),(68±7),(128±17),(155±20)μg.h.mL-1和(193±36)μg.h.mL-1;AUC0-∞分别为(34±5),(71±10),(135±19),(164±21)μg.h.mL-1和(206±38)μg.h.mL-1,方差分析结果表明各剂量的主要药动学参数t1/2,tmax和AUC0-24等性别间差异均无统计学意义,但t1/2和MRT0-24随服药剂量的增加而延长。多次口服米屈肼胶囊后,t1/2为(14.6±2.5 h),MRT0-24为(21.4±3.5)h,tmax为(1.0±0.3)h,CSmSax为(24±4)μg.mL-1,CSmSin为(9.3±1.6)μg.mL-1,C珚SS为(12.9±2.2)μg.mL-1,血药浓度波动度DF为(1.2±0.2),蓄积系数R为(3.3±0.5),AUCS0S-8为(116±20)μg.h.mL-1。统计分析结果显示多次给药后t1/2,tmax,Cmax,C珚SS,DF和AUCS0S-8等性别间差异均无统计学意义。但t1/2和MRT0-24与单次给药500mg剂量给相比明显�
OJECTIVE To assess the pharmacokinetics and tolerance of single and multiple-dose mildronate in healthy Chi nese subjects. METHODS Forty healthy subjects were divided into five groups （each group consisting 4 males and 4 females） by randomized blind design. These five groups were administered single-dose of 250, 500, 1 000, 1 250 or 1 500 mg mildronate capsule respectively for tolerablity assessment and single-dose pharmacokinetics profile. After one week washout period, the subjects of 500 mg dose group in single-dose pharmacokinetics study were enrolled for a multiple-dose pharmacokinetics profile. Eight volunteers were received mildronate at 500 mg every 8 h （q 8 h） for consecutive 13 days. Safety and tolerance were evalu ated by monitoring adverse events and laboratory parameters and pharmacokinetics were assessed by determining mildronate concentrations with a validated HPLOMS method. RESULTS No serious adverse events occurred. After single dose oral ad ministration, the main pharmacokinetic parameters found for mildronate at doses of 250, 500, 1 000, 1 250 mg and I 500 mg were as follows：tmax were （ 1.2 ± 0. 3）, （ 1.0 ± 0. 4）, （ 1.2 ± 0. 6）, （ 1.2 ± 0. 4）h and （ 1.0 ± 0. 4）h, respectively; t1/2 were （3.6 ±0. 7）,（5.3± 1.2）,（6. 1 ±0. 5）, （6.1 ±0. 4）h and （6. 6±0. 9）h;MRTo 24 were （7. 3±0. 9）, （8. 4± 1.1）,（8. 7± 1.5）,（8. 7± 0. 7）h and （9. 0± 1.1）h;V/F were （39± 7）,（54± 12）, （66± 9）,（68 ± 7） L and （71 ± 14） L;CL/F were （7. 6± 1.2）, （7. 2 ± 1.1）,（7.5±l.1）,（7.8±1.0）L.h -1 and （7.5±1.3） L.h -1; Cmax were （5.9±0.9）,（13.8±3.2）, （30.4±6.3）,（35.5±13.1）μg.mL-1and （46.3± 14. 1）/2g.mL-1; AUG, 2g were （32±6）,（68±7）,（128± 17）,（155 ±20）μg.h.mL-1 and （193± 36）μg.h.mL-1 ; AUC0-∞ were （34 ± 5）, （71 ± 10）, （135 ± 19）, （164 ± 21 ）μg.h.mL-1 and （206 ± 38）μg.h.mL- 1 , respectively. ANOVA analyses showed that no signif
出处
《中国医院药学杂志》
CAS
CSCD
北大核心
2013年第1期15-19,共5页
Chinese Journal of Hospital Pharmacy
关键词
米屈肼
单剂量
多剂量
耐受性
药动学
mildronate
single-dose
multiple-dose
tolerability
pharmacokineticssilver nanoparticle
purification
uhrafil tration
