Drug-Drug Interaction Between Eugenol and Repaglinide in Type 2 Diabetes Mellitus and Its Potential Mechanism.

This study investigated the potential drug-drug interaction (DDI) between eugenol (EUG) and repaglinide (RPG) in type 2 diabetes mellitus (T2DM). A T2DM rat model was established using a high-fat diet and streptozotocin (STZ). The single-dose group received 0.4 mg/kg RPG, and co-administration groups were pre-treated with EUG (50, 100, 150 mg/kg) for seven days before receiving a single dose of RPG (0.4 mg/kg). The blood glucose and pharmacokinetic parameters of RPG were assessed in the plasma samples of rats. The effect of EUG on RPG metabolic stability and cytochrome P3A (CYP3A) activity was evaluated in rat liver microsomes (RLM). In T2DM rats, RPG treatment showed a hypoglycemic effect, which was further promoted by EUG co-administration in a dose-dependent manner (p < 0.001). EUG co-administration affected the pharmacokinetics of RPG by increasing the area under the curve (AUC, increased 88.64%, 164.59%, and 244.72% vs single RPG, p < 0.001), plasma maximum concentration (Cmax, increased 18.61%, 53.58%, and 77.63% vs single RPG, p < 0.01), maximum concentration (Tmax, 1.0 h for EUG co-administration vs 0.5 h for single RPG), half-life (t1/2, prolonged 33.86%, 49.61%, and 88.19% vs single RPG, p < 0.01), mean retention time (MRT, prolonged 17.62%, 26.42%, 44.04% vs single RPG, p < 0.001), and decreased the clearance rate (Clz/F, decreased 48.92%, 63.31%, and 74.10% vs single RPG, p < 0.001) in a dose-dependent manner. In vitro RLM study, EUG improved the metabolic stability of RPG by prolonging the half-life (44.09 ± 3.25 min) and reducing the intrinsic clearance (30.55 ± 3.69 µL/min/mg protein). EUG also inhibited the activity of CYP3A with an IC50 of 7.90 ± 1.79 µM. Co-administration of EUG promoted the hypoglycemic effect of RPG through enhancing RPG systemic exposure in T2DM rats, potentially by improving RPG metabolic stability and inhibiting CYP3A activity.