IMPROVED BIOAVAILABILITY OF LINAGLIPTIN BY RESVERATROL IN RATS- INVOLVEMENT OF PERMEABILITY GLYCOPROTEIN (P-gp) INHIBITION

The maintenance of an appropriate serum concentration of a drug is important to ensure therapeutic efficacy. Functional alterations of drug transporters may influence the serum concentration of drugs through changes in its pharmacokinetics and pharmacodynamics (PK/PD). In this study, we have focused on the influence of functional alterations in the intestinal P-glycoprotein (P-gp) on the PK of linagliptin (LIN) by the oral route under normal and diabetic conditions before and after pretreatment with resveratrol (RSV) and verapamil (VER) as standard. The interaction between LIN and RSV has been studied using in-vitro noneverted sac study, in-situ Single-Pass Intestinal Perfusion (SPIP) study, and in-vivo oral bioavailability study in rats. Pretreatment with RSV significantly enhanced the intestinal transport, apparent permeability, and effective permeability of LIN in normal and diabetic rats indicating the active role of P-gp in LIN absorption. Pretreatment with RSV significantly altered the C_max and AUC of LIN in both normal and diabetic rats. But compared to normal rats, diabetic rats show a significant decrease in intestinal transport, and increased oral bioavailability of LIN indicates that the expression of P-gp is increased in diabetic conditions. In conclusion, the oral bioavailability of LIN is improved with RSV, and this combination is beneficial for the better control of diabetes, and further studies are needed to confirm the results in patients.