The effect of verapamil on the pharmacokinetics of saxagliptin in healthy and type 2 diabetes modeled rats

Diabetes Mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia and a complete or partial deficiency in insulin secretion. Type 2 Diabetes Mellitus (T2DM), which is characterized by a partial decrease in insulin secretion and/or insulin resistance in peripheral tissues, and accounts for approximately 90% of diabetes cases. Cardiovascular side effects are shown as the most important cause of hospitalization and death in T2DM patients. Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is recommended for use in T2DM patients to achieve glycemic control. Verapamil, a calcium channel blocker, is recommended for use in cardiovascular disorders such as hypertension, supraventricular tachyarrhythmia and angina pectoris. In this study, it was aimed to investigate the effect of verapamil on the pharmacokinetics of saxagliptin in healthy and T2DM modeled rats. In addition to the four pharmacokinetic study groups (n=192), a total of 212 male Wistar Albino rats with method validation studies (n=20) were used in the study. Healthy saxagliptin (HS, n=48), healthy verapamil + saxagliptin (HVS, n=48), diabetic saxagliptin (DS, n=48) and diabetic verapamil + saxagliptin (DVS, n=48) groups formed the pharmacokinetic study groups. In addition, blood glucose levels were investigated to determine pharmacodynamic differences in pharmacokinetic study groups. Verapamil was administered to the rats in the interaction groups at a dose of 10 mg/kg for seven days, and saxagliptin was administered orally to all groups at a single dose of 20 mg/kg on the eighth day with the help of gastric gavage. Plasma saxagliptin and 5-hydroxy saxagliptin (5-HS) levels were determined using high pressure liquid chromatography-UV. The non-compartmental method was used to calculate the pharmacokinetic parameters. The half-life (t1/2λz) of saxagliptin in the HS group was 3,97 hours, area under the curve (AUC0-∞) value 22,84 h*μg/mL, mean residence time (MRT0-∞) 5,11 hours, total clearance (Cl/F) 875,3 mL/hr/kg, volume of distribution (Vdarea/F) 5017,51 mL/kg, The peak concentration (Cpeak) was 4,8 ± 1,07 μg/mL and the time to reach the peak concentration (Tpeak) was 1,5 hours. With the combined effect of diabetes and verapamil, an increase was observed in the t1/2λz and AUC0-∞ values of saxagliptin, while a decrease was observed in the Cl/F value. Verapamil administration and the presence of a diabetic condition caused an increase in the Cpeak value of saxagliptin and a decrease in the Tpeak value. The values of Metabolite to Parent drug Ratio [MPR: (EAA0-∞(5-HS) / EAA0-∞(Saxagliptin))] were determined as 2,85; 1,5; 2,09 and 1,01 among the HS, HVS, DS and DVS groups, respectively. It was determined that blood glucose levels decreased in all groups with saxagliptin administration, and the decrease was higher in the groups treated with verapamil pre-treatment. The contribution of verapamil to the reduction in blood glucose levels was statistically significant in diabetic rat groups at a higher number of sampling times compared to healthy rat groups. In diabetic patients, verapamil may increase the therapeutic efficacy of saxagliptin. However, since saxagliptin was used in a single dose and was performed on a limited number of rats in this study, determining the pharmacokinetic and pharmacodynamic data with the results that will occur with repeated administration in different populations and determining the mechanisms by which these results are shaped will contribute to the use of saxagliptin and verapamil in T2DM patients.