单次不同剂量PEG400对大鼠体内细胞色素P450 3A活性的影响

 目的研究单次不同剂量聚乙二醇(PEG)400对大鼠体内细胞色素P4503A活性的影响。方法以咪哒唑仑为探针,HPLC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,以不同剂量PEG400处理组与阴性对照组的AUC_0-4h比值为指标,研究它们对大鼠体内细胞色素P4503A药酶活性的影响。结果与生理盐水组相比,PEG400(15mg·kg^-1)、PEG400(60mg·kg^-1)分别显著增加咪哒唑仑AUC_0-4h 1.98,1.75倍(P<0.05),显著降低1′-羟基咪哒唑仑与咪哒唑仑AUC_0-4h的比值,分别从1.09降至0.26和0.28(P<0.05)。结论两种剂量PEG400对CYP3A均有明显的抑制作用。

Effects of PEG400 on Activity of Cytochrome P450 3As in Rat

OBJECTIVE To evaluate the effects of PEG400 on the activity of CYP3As in rat in vivo.METHODS Using midazolam as a probe,pharmacokinetic parameters of midazolam and its metabolite 1'-hydroxymidazolam were estimated from the plasma concentrations determined by HPLC.The ratio of 1'-OHMDZ to MDZ AUC0-4 h was used to detect changes of CYP3A4 activity.RESULTS The pharmacokinetics parameters showed that single dose administration of PEG400(15 mg·kg^-1),PEG400(60 mg·kg^-1) significantly increased midazolam AUC_{0-4 h} by 1.98,1.75-fold(P<0.05),respectively,and significantly decreased the AUC_{0-4 h} ratios of 1'-OH-MDZ to MDZ from 1.09 to 0.28 and 0.26(P<0.05),respectively.CONCLUSION This study indicated that two different doses of PEG400 with single administration had significant inhibition on CYP3A.Therefore,PEG400 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 effects.