Drug-Drug Interactions: Influence of verapamil on the pharmacokinetics of sitagliptin in rats and Ex vivo models

P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) play a significant role in the disposition and elimination of drugs. The objective of this study was to investigate the mechanism underlying the interaction between sitagliptin (substrate of P-gp and CYP3A4) and verapamil (known modulator of P-gp and CYP3A4) using in vivo, ex vivo and in situ models. Rats were treated with sitagliptin (10 mg/kg, oral and/or 5 mg/kg, intravenous) alone and in combination with verapamil (40 mg/kg, oral) for 15 consecutive days. Blood samples were collected from the tail vein on 1st day in single dose pharmacokinetic study (SDS) and on 15th day in multiple dose pharmacokinetic study (MDS). The plasma concentrations of sitagliptin were significantly higher in the verapamil pretreated group when compared to sitagliptin control group. Verapamil pretreatment significantly increased the mean area under the plasma concentration-time curve from 0 to 24h (AUC0-24h), peak plasma concentration (Cmax), percent absolute bioavailability (AB%), elimination half-life (t1/2) and decreased the volume of distribution (Vz/F), clearance (CL/F) and apparent volume of distribution at steady state (Vss/F) of sitagliptin in both SDS and MDS (oral and intravenous). Ex vivo study results showed that the apparent permeability coefficient (Papp), net efflux and efflux ratio values were significantly increased by the known P-gp and CYP3A4 inhibitors (itraconazole and ketoconazole) and verapamil. In single pass intestinal perfusion (In situ) study, the effective permeability coefficient (Peff) and intestinal absorption rate constant (Ka) were increased in the presence of verapamil (p<0.05). The present study results revealed that verapamil enhanced the bioavailability of sitagliptin probably by inhibiting its absorption via P-gp and/or the CYP3A4-mediated biotransformation in rats. Verapamil can be co‐administered with sitagliptin without dose adjustment due to high safety margin of sitagliptin.