多次不同剂量PEG 400对大鼠体内细胞色素P450 3A活性的影响  

Effect of two different doses of PEG400 with multiple administration on the activity of cytochrome P450 3As in rat

作　　者：任秀华[1,2] 斯陆勤[1] 曹磊[1] 姚洁[1] 裘军[1] 李高[1] 

机构地区：[1]华中科技大学同济医学院药学院药剂教研室,湖北武汉430030 [2]华中科技大学同济医学院附属同济医院药学部,湖北武汉430030

出　　处：《中国医院药学杂志》2008年第22期1912-1916,共5页Chinese Journal of Hospital Pharmacy

基　　金：国家自然科学基金资助项目(编号:30572265)

摘　　要：目的:研究多次不同剂量PEG400对大鼠体内细胞色素P450 3A活性的影响。方法:以咪哒唑仑为探针,HPLC法测定咪哒唑仑及其代谢物1′-羟基咪哒唑仑在大鼠体内的血药浓度并计算其药动学参数,以多次不同剂量PEG400处理组与阴性对照组的AUC0-4h比值为指标,研究它们对大鼠体内细胞色素P450 3A药酶活性的影响。结果:与生理盐水组相比,PEG400(5mg.kg-1,tid,3d)、PEG400(20mg.kg-1,tid,3d)分别增加咪哒唑仑AUC0-4h(1.9±0.5)(P<0.05)、(1.14±0.21)倍,显著降低1′-羟基咪哒唑仑与咪哒唑仑AUC0-4h的比值,分别从(1.09±0.22)降至(0.27±0.11)和(0.58±0.14)(P<0.05)。结论:2种剂量PEG400对CYP3A均有明显的抑制作用,PEG400(5mg.kg-1,tid,3d)显著增加咪哒唑仑的生物利用度。OBJECTIVE To evaluate the effect of PEG400 on the activity of CYP3As in rat in vivo. METHODS Using midazolam as a probe, pharmacokinetics parameters for midazolam and its metabolite 1′-hydroxymidazolam were estimated from the plasma concentrations determined by HPLC. The ratio of 1′-OHMDZ/MDZ AUC0-4h was used to detect changes in CYP3A4 activity. RESULTS The pharmacokinetics parameters showed that multiple dose administration of PEG400 （5 mg·kg^-1, tid, 3 d）, PEG400 （20 mg·kg^-1, tid, 3 d） increased midazolam AUC0-4h 1.91-（P〈0. 05）, 1.14-fold, respectively, and significantly decreased the ratios of 1′-OH-MDZ/MDZ AUC0-4h from 1.09 ± 0. 22 to 0. 27 ± 0. 11 and 0. 58 ± 0. 14（P〈0. 05）, respectively. CONCLUSION This study indicates that two different doses of PEG400 with multiple administrations show significant inhibi tion on CYP3A. PEG 400 （5 mg·kg^-1, tid, 3 d） could increase the bioavailability of midazolam. Therefore, PEG 400 might be used to prepare drug formulations in pharmaceutical industry and would increase the bioavailability of some drugs transformed by CYP3As and further lead to significant clinical pharmacologic effect.

关 键 词：CYP3A PEG 400 咪哒唑仑 高效液相色谱法 药动学 

分 类 号：R927.2[医药卫生—药学]