Pharmacokinetic interaction of saxagliptin with andrographolide and their hypoglycemic effect in type 2 diabetes rats

Controlling blood glucose is the primary therapeutic strategy for T2DM. Both saxagliptin and andrographolide possess hypoglycemic effects, which makes the combination easy. This study aimed to evaluate the co-administration of saxagliptin and andrographolide in rats and revealed their combined impact on type 2 diabetes (T2DM). T2DM rat models were established by high-fat diet and the injection of nicotinamide and streptozotocin. The blood glucose and insulin resistance index were monitored after modeling. The pharmacokinetics of saxagliptin was assessed by orally administrating 10 mg/kg saxagliptin. The co-administration was performed with the pre-treatment of 30 or 100 mg/kg andrographolide. In vitro, the metabolic stability of saxagliptin was assessed in rat liver microsomes. The co-administration of saxagliptin with andrographolide induced significant changes in the pharmacokinetics of saxagliptin, behaving as the increasing AUC(0-t), Cmax, t1/2, and the decreasing clearance rate. The effect of andrographolide was enhanced with the growing concentration. Combination with andrographolide enhanced the hypoglycemic effect and alleviated insulin resistance of saxagliptin in T2DM rats. Co-administration of saxagliptin with 100 mg/kg andrographolide induced hypoglycemia. In vitro, andrographolide significantly improved the metabolic stability of saxagliptin and showed a significant inhibitory effect on the activity of CYP3A4. Combining saxagliptin with andrographolide could increase the systemic exposure of saxagliptin via inhibiting CYP3A4 and improve the hypoglycemic effect, but the high concentration of andrographolide is the risk of inducing hypoglycemia.