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

Abstract

Backgrond: Astragaloside IV (AST) and metoprolol are often used together to treat cardiovascular diseases, while the herb-drug interaction (HDI) between them is still unclear.

Objective: This study investigates the effect of AST on the pharmacokinetics of metoprolol in rats and its mechanism to predict the HDI.

Method: First, IC50 value of AST on nine CYP450 enzymes in human liver microsomes (HLMs) was determined by the cocktail method. 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 they received metoprolol (27 mg/kg) by oral administration. Blood samples were determined using HPLC. Finally, the mechanism of AST was explored.

Results: AST exhibited a moderate inhibitory effect on CYP2D6 with IC₅₀ value of 32.28 μM. The pharmacokinetic parameters of metoprolol were significantly altered by AST with the increase of AUC_0-∞ (538.81 ± 51.41 to 1088.34 ± 86.46 μg*min/mL, P<0.05) and C_max (6.21 ± 0.56 to 8.34 ± 0.87 μg/ml, P<0.05). The investigation of the mechanism showed AST to be an irreversible inhibitor of CYP2D6 with K_I value of 2.9 μM and K_inact of 0.018 min^-1, respectively.

Conclusion: AST was found to increase the plasma exposure of metoprolol in rats. AST reduced the metabolism of metoprolol by inhibiting CYP2D6 activity. The HDI might enhance when metoprolol and AST will be applied in combination.

Keywords: Astragaloside IV; CYP2D6; herb-drug interaction; irreversible inhibition; metoprolol; pharmacokinetics.