咪达唑仑直肠凝胶剂在兔体内的药代动力学及绝对生物利用度研究  

Pharmacokinetics and the absolute bioavailability of midazolam rectal gel in rabbits

作　　者：段月晓[1] 李倩[1] 郑爱萍[2] 朱晓薇[1] 

机构地区：[1]天津中医药大学研究生部,天津300193 [2]军事医学科学院毒物药物研究所六室,北京100850

出　　处：《国际药学研究杂志》2013年第3期338-343,共6页Journal of International Pharmaceutical Research

基　　金：国家"重大新药创制"科技重大专项资助项目(2011ZXJ09103-09B;2012ZX09301003-001-009)

摘　　要：目的研究咪达唑仑直肠凝胶剂在新西兰白兔体内的药代动力学和绝对生物利用度(F)。方法采用双周期自身交叉设计,即健康新西兰白兔6只,雌雄各半并按雌雄分为两组,分别采用单剂量静脉注射3 mg/kg参比制剂(咪达唑仑注射液)直肠给予3 mg/kg受试制剂(咪达唑仑直肠凝胶剂)两种给药方式,交叉给药,间隔1周。并于给药后不同时间点取血,采用HPLC法测定血浆中咪达唑仑的浓度,利用DAS 2.0软件估算咪达唑仑在新西兰白兔体内的药动学参数,并计算F值。结果新西兰白兔静脉注射3 mg/kg咪达唑仑注射液后,体内药-时曲线符合二房室模型,Tmax为2 min,Cmax为(2 412.2±548.3)μg/L,t1/2β为(30.8±13.2)min,AUC0～4 h为(89 956.9±33 045.8)μg.min/L,AUC0～∞为(91 638.1±33 777.2)μg.min/L。直肠给予3 mg/kg咪达唑仑凝胶剂后,体内药-时曲线存在双峰现象,且符合二房室模型,Tmax分别为12和20 min,Cmax分别为(745.7±472.6)和(846.2±390.0)μg/L,t1/2β为(32.2±10.1)min,AUC0～4 h为(66 647.0±39 748.4)μg.min/L;AUC0～∞为(69 564.5±40 761.5)μg.min/L。以AUC0～4 h计算,咪达唑仑凝胶剂的F值约为(74.1±19.1)%。结论咪达唑仑直肠凝胶剂在兔体内起效快,迅速分布和消除,生物利用度高,在临床能产生较好的疗效,具有一定的开发价值。Objective To investigate the pharmacokinetics and absolute bioavailability of midazolam rectal gel in New Zealand white rabbits.Methods By applying double cycle self crossover design,6 health New Zealand white rabbits,3 male and 3 female were divided into two groups according to their sex.They were administrated a single dose of intravenous 3 mg / kg reference preparation（midazolam injection） or rectal given 3 mg/kg subjects preparation（midazolam rectal gels） respectively,cross to medicine,at an interval of one week.Blood samples were collected before and at different intervals after midazolam administration.The concentration of midazolam in rabbit plasma was determined by HPLC method.The pharmacokinetic parameters were estimated by DAS 2.0 pharmacokinetic program.The absolute bioavailability was calculated.Results The concentration-time curves of intravenous 3 mg / kg midazolam administration fitted to two compartment model.Tmax was 2 min,Cmax was（2 412.2 ± 548.3） μg / L,t1 /2β was（30.85 ± 13.20） min,AUC0 ～ 4 h was（89 956.9 ± 33 045.8） μg.min / L,AUC0 ～ ∞ was（91 638.1 ± 33 777.2） μg.min / L.The concentration-time curves of rectal given 3 mg / kg midazolam administration showed bimodal phenomenon and fitted to two-compartment model.Tmaxwere 12 and 20 min,Cmax were（745.7 ± 472.6） and（846.2 ± 390.0） μg / L,respectively.The t1 /2β was（32.2 ± 10.1） min,AUC0 ～ 4 h was（66647.0 ± 39748.4） μg.min / L;AUC0 ～ ∞ was（69564.5 ± 40761.5） μg.min / L.As by calculated AUC0 ～ 4 h,the mean absolute bioavailability of midazolam rectal gel was（74.1 ± 19.1） %.Conclusion Midazolam rectal gels work fast in rabbits,distribute and eliminate rapidly,and have a high absolute bioavailability.It can produce a good curative effect in potential and has a certain development value.

关 键 词：咪达唑仑 高效液相色谱法 药代动力学 绝对生物利用度 兔 

分 类 号：R96[医药卫生—药理学]