Effects of Astragaloside IV on the Pharmacokinetics of Metoprolol in Rats and its Mechanism

Backgrond: Astragaloside IV (AST) and metoprolol are often used together to treat cardiovascular disease, while the potential of herb-drug interaction (HDI) between them is still unclear.This study investigates the effect of AST on the pharmacokinetics of metoprolol in rats and its mechanism to predict the potential of HDI.First, IC50 of AST on nine CYP450 enzymes in human liver microsomes (HLMs) was determined by the cocktail method. Then, we explored the effect of AST on the pharmacokinetics of metoprolol (metabolized by CYP2D6) in vivo. Twelve male SD rats were equally divided into two groups, with or without pretreatment of AST (3 mg/kg/day) for 7 days, and received metoprolol (27 mg/kg) by oral administration. Blood samples were determined using HPLC. Finally, its mechanism was explored.AST exhibited a moderate inhibitory effect on CYP2D6 with IC50 of 32.28 µM. The pharmacokinetic parameters of metoprolol were significantly altered by AST with the increase of AUC0-∞ (538.81 ± 51.41 to 1088.34 ± 86.46 µg*min/mL, P<0.05) and Cmax (6.21 ± 0.56 to 8.34 ± 0.87 µg/ml, P<0.05). The investigation of the mechanism showed AST was an irreversible inhibitor of CYP2D6 with KI of 2.9 µM and Kinact of 0.018 min-1, respectively.It indicated that AST could increase the plasma exposure of metoprolol in rats. The mechanism might be that AST reduced the metabolism of metoprolol by inhibiting CYP2D6 activity. The potential of HDI might occur when they were applied in combination.