Ferulic Acid Dose Effect on Pharmacokinetics of Glimepiride and its Metabolite Hydroxy Glimepiride in Rats

Background: To mitigate diabetes and its complications in cardiovascular diseases, the antidiabetic agent Glimepiride (GLM) is usually administered with Ferulic Acid (FA) concomitantly in clinical settings. However, both drugs are prone to be metabolized partly by CYP2C9; thus, they have the potential drug-drug interaction affecting safety and efficacy. Objective: This study aimed to evaluate the Pharmacokinetic (PK) effects of ferulic acid on glimepiride and its metabolite hydroxy glimepiride (OH-GLM) in plasma by using the HPLCMS/ MS method. Methods: Healthy male Sprague Dawley (SD) rats were randomly divided into three groups and received intragastric administration of 0.5% sodium Carboxymethyl Cellulose (CMC), low-dose of FA (20 mg•kg^-1 ), and high-dose of FA (40 mg•kg^-1) for 8 days, respectively. Rats were given 0.5% sodium CMC or FA on the last day and then uniformly given 1.0 mg•kg^-1 glimepiride by gavage. Blood samples were obtained from retro-orbital plexus at the time points of 0.167, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after administration. Plasma samples were analyzed for GLM and its metabolite OH-GLM on an HPLC-MS/MS system. Results: No statistically significant difference was found in the effect of low-dose of FA on the pharmacokinetics of GLM. However, high-dose of FA significantly decreased Cmax of GLM by 30.05% and CLz/F of OH-GLM by 47.45% and increased Tmax and t1/2z of GLM by 95.87% and 140.00%, respectively. Conclusion: Low-dose of FA did not alter GLM metabolism, while high-dose treatment of FA apparently caused pharmacokinetics interaction with GLM in rats.