Drug-drug Interaction Between Alpinetin and Glimepiride and its Potential Mechanism in Rats

Given that alpinetin possesses hypoglycemic and cardioprotective properties, it holds potential for co-administration with the antidiabetic agent glimepiride. The aim was to evaluate the impact of alpinetin on the pharmacokinetics and hypoglycemic efficacy of glimepiride, thereby providing a foundation for the development of alpinetin and informing its potential clinical translation. Pharmacokinetic studies were performed in rats following oral administration of glimepiride (1 mg/kg) alone or combined with alpinetin (30 mg/kg). The effect of the combination of glimepiride and alpinetin on blood glucose levels was investigated in a rat model of type 2 diabetes mellitus (T2DM). In vitro experiments were conducted to evaluate the effect of alpinetin on glimepiride metabolic stability and to assess its role on cytochrome P450 2C9 (CYP2C9) activity. Co-administration of glimepiride with alpinetin resulted in significant changes in the pharmacokinetics of glimepiride, as evidenced by an increase in area under the concentration-time curve (AUC), elimination half-life (t_1/2), maximum concentration (C_max), and a decrease in clearance. Glimepiride in combination with alpinetin enhanced the hypoglycemic effect in T2DM rats. Mechanistic studies in liver microsomes revealed that alpinetin improved glimepiride metabolic stability and inhibited CYP2C9 activity. The combination of glimepiride with alpinetin may increase the systemic exposure of glimepiride through inhibition of CYP2C9 activity. This likely contributes to the enhanced hypoglycemic effect observed, but also underscores the need for caution regarding the potential risk of hypoglycemia.