左旋奥硝唑剂量递增人体耐受性及药动学研究  

Tolerability,Safety and Pharmacokinetics of(S)-Ornidazole in Ascending Dose Study in Healthy Chinese Volunteers

作　　者：赵亚男[1] 吴佩[1] 孙华[1] 杨菁菁[1] 过怿赟[1] 柳晓泉[2] 

机构地区：[1]皖南医学院弋矶山医院国家药物临床试验机构,安徽芜湖241001 [2]中国药科大学药物代谢与动力学中心,南京210009

出　　处：《中国药学杂志》2011年第6期454-457,共4页Chinese Pharmaceutical Journal

基　　金：国家火炬计划重点项目(Z20050041);国家重大专项项目(2008ZX09101)

摘　　要：目的研究中国健康志愿者静脉滴注左旋奥硝唑剂量递增的耐受性、安全性及药动学。方法 20名健康男性、20名健康女性受试者按体重分层随机分入4组,分别接受500,1 000,1 250,1 500 mg单次用药试验;单次用药试验结束清洗2周后,500 mg剂量组再次接受每天早、晚500 mg连续5 d的多次用药试验;1 000 mg剂量组再次接受1 000 mg奥硝唑(阳性对照比较不良反应)的单次用药试验。观察不良事件,HPLC测定血浆中左旋奥硝唑浓度,BPSS2.0计算主要药动学参数。结果单次静脉滴注左旋奥硝唑500,1 000,1 250,1 500 mg的不良反应为0/9,0/10,0/10,2/10;多次静脉滴注左旋奥硝唑500 mg的不良反应为3/10;单次静脉滴注消旋奥硝唑1 000 mg的不良反应为5/10。单次用药500,1 000,1 500 mg,多次用药500 mg的ρmax分别是(8.63±2.57),(18.6±4.08),(27.5±10.6),(23.4±4.67)mg·L-1;AUC0-60分别为(109.5±24.0),(293.1±69.9),(422.9±84.0),(412.3±99.4)mg.h.L-1。结论中国健康志愿者静脉滴注左旋奥硝唑500～1 500 mg单剂量,500mg多剂量是安全,能够耐受的;500～1 500 mg内呈线性药动学特征,多次用药后体内有一定蓄积。OBJECTIVE To study the tolerability, safety and pharmacokinetics of （S）-ornidazole after ascending intravenous infusion doses in healthy Chinese volunteers. METHODS 40 Healthy male and female Chinese volunteers were randomized into 1 （ male-female = 1：1 ） of 4 treatment groups to receive a single dose of 500, 1 000, 1 250 or 1 500 mg （S） -ornidazole, respectively. Multiple doses （500 mg bid） of （S） -ornidazole were administered for 5 consecutive days after a 2-week washout period of 500 mg single-dose （S）-ornidazole. A single dose of 1 000 mg （R ,S）-ornidazole was administered as the positive control after a 2-week washout period of 1 000 mg single-dose （S）-ornidazole. Adverse events were observed and （S）-ornidazole concentrations in plasma were deter- mined using HPLC-UV. The major pharmacokinetic parameters were calculated by BPSS2.0. RESULTS The incidence rates of adverse reactions after single-dose intravenous infusion of 500, 1 000, 1 250, and 1 500 mg （S）-ornidazole were 0/9, 0/10, 0/10, and 2/10, respectively, and 3/10 following multiple doses of 500 mg （S）-ornidazole and 5/10 following a single dose of ernidazole. The main pharmacokinetic parameters of single-dose （S）-ornidazole 500, 1 000, 1 500 mg or multiple-dose 500 mg were as follows： ρmax （8.63± 2. 57）, （ 18.6 ± 4. 08 ）, （27. 5 ± 10. 6）, （23.4 ± 4. 67 ）mg·L^-1, respectively. AUC0-60 （ 109. 5 ± 24. 0 ）, （ 293.06 ± 69. 9）, （422. 9 ± 84.0）, （412. 3 ±99.4） mg·h·L^-1 , respectively. CONCLUSION （S） -ornidazole was well tolerated in Chinese heahhy volunteers after single-dose intravenous infusion of 500 to 1 500 mg and multiple-dose of 500mg. The pharmaeokinetics is linear over the range of 500 to 1 500 mg with accumulation after multiple doses of 500 mg.

关 键 词：左旋奥硝唑 消旋奥硝唑 耐受性 药动学 

分 类 号：R969.1[医药卫生—药理学]