Sitagliptin with Piperine Pharmacodynamic and Pharmacokinetic Studies in Normal and Diabetic Rabbits

Abstract

Background: Food-drug interactions caused by dietary alkaloids like piperine may significantly impact medication metabolism and excretion. In this study, we studied piperine's effect on sitagliptin's PD and PK. Method: The research assessed the food-drug interaction in normal and diabetic rabbits to demonstrate how piperine affects the PD and PK of sitagliptin. Piperine, sitagliptin, and sitagliptin plus piperine treatment were administered to normal and diabetic rabbits. Blood samples were taken from the treated rabbits at predetermined intervals on days 1, 3, 7, and 21. Plasma was extracted from the obtained blood samples, and glucose levels were measured by the GOD-POD technique and insulin levels by ELISA. The extracted plasma samples collected on days 1 & 21 at predetermined intervals were exposed to HPLC analysis for estimation of PK parameters of sitagliptin. In both normal and diabetic rabbits, statistically comparisons were done between PK/PD of sitagliptin alone and in combination with piperine. Results: Piperine plus sitagliptin has no significant difference in glucose levels, percent blood glucose reductions, and insulin levels on 0, 1, 3, 7, 14 & 21st days in normal rabbits as compared with sitagliptin alone, and this may be because sitagliptin has no hypoglycemic effect. In diabetic rabbits, sitagliptin plus piperine significantly reduced blood glucose levels, raised the percent blood glucose reductions, and increased insulin levels on days 1, 3, 7, 14, and 21, compared with sitagliptin alone, demonstrating antihyperglycemic efficacy. Antihyperglycemic efficacy results indicate that sitagliptin with piperine has an additive effect on releasing more insulin, which is considered a PD interaction. In the PK study, sitagliptin plus piperine significantly raised the AUC0-∞, AUC0-t, AUMC0-∞, and AUMC0-t and lowered the CL of sitagliptin compared to sitagliptin alone on days 1 and 21 in normal and diabetic rabbits. Furthermore, the Tmax of sitagliptin did not change significantly, and the Ke, t1/2, and MRT varied non-significantly when piperine was administered concurrently. Additionally, Vd was also non-significantly altered in normal rabbits. This study's results suggest that piperine inhibits the CYP3A4 metabolic enzyme and P-gp (P-glycoprotein) substrate of sitagliptin in normal and diabetic rabbits, indicating a food-drug interaction. Conclusion: In normal rabbits, this study found no PD interaction. A PD interaction between piperine and sitagliptin showed the additive effect in diabetic rabbits by showing an antihyperglycemic activity. As per study findings, in normal and diabetic rabbits, piperine significantly increased the bioavailability of sitagliptin. However, the anticipated clinical response in humans cannot always be predicted from animal studies, so further research is required to evaluate drug interaction in humans.