The Effect Of Astragaloside â…£ On The Activity Of CYP1A2in Vitro And In Rats

Objective:In this study, we investigated the effect of Astragaloside Ⅳ(AGS-Ⅳ) on the activity of CYP1A2in rat liver microsomes and in rats.Methods:The effect of AGS-Ⅳ on CYP1A2activity was investigated using probe substrates:phenacetin in vitro and theophylline in vivo. Phenacetin was incubated in rat liver microsomes with or without AGS-Ⅳ, the mechanism, kinetics were determined. The inhibitory effect of AGS-Ⅳ on CYP1A2activity in rats was also determined using theophylline in vivo. The pharmacokinetics of theophylline were observed after a single or week-long treatment with AGS-Ⅳ. HPLC was used to determine model substrates and metabolites.Results:The inhibitory effect of AGS-Ⅳ on CYP1A2activity depended on the amount of AGS-Ⅳ in the reaction mixture. AGS-Ⅳ inhibited the activity of CYP1A2at an IC50value of45μM. AGS-Ⅳ was a competitive inhibitor having no time-dependent inhibition with Ki value of6.29μM. In the multiple-pretreatment rats group, it were found to have a significantly higher area under the concentration-time curve (AUC) for theophylline, as well as a lower apparent oral total body clearance value (CL/F). In contrast, no significant difference in metabolism of theophylline was found for the single pretreatment group.Conclusion:These findings suggest AGS-Ⅳ is a potent inhibitor of CYP1A2. Multiple pretreatment with AGS-Ⅳ can reduce theophylline clearance. This may result from competitive inhibition of CYP1A2activity. This study provides a useful reference for the reasonable and safe use of herbal or natural products containing AGS-Ⅳ to avoid unnecessary herb-drug interactions.