Objective: The aim of this study was to establish a pharmacokinetic/pharmacodynamic (PK/PD) link model using NONMEM 7.2, and to quantitatively investigate the influence of sitagliptin on streptozotocin(STZ)-induced diabetic rats DPP-4 activity, plasma insulin concentration and blood glucose level.Methods: The animal model of type 2 diabetic rats (Sprague Dawley) was set up through intraperitoneal injection of 50mg/kg STZ.A reversed-phase high performance liquid chromatography method with UV detection was introduced for determination of sitagliptin in diabetic rats.The plasma DPP-4 activity, insulin concentration and blood glucose level in diabetic model rats was measured after oral administration of sitagliptin at the doses of 0, 1, 5 and 10 mg/kg.The mechanism-based PK/PD model was established by NONMEM 7.2 in according with pharmacology of sitagliptin.Results: The pharmacokinetics of sitagliptin was fitted well with a one-compartment model, and the blood concentrations of sitagliptin employed in the final PK/PD model were simulated from the PK model.An Emax model was adopted to describe the inhibition of plasma DPP-4 activity by sitagliptin, and the maximal efficacy (Emax) was estimated as 0.905; the 50% efficacy concentration of sitagliptin (EC50) was 0.107 mg/L and the shape factor γ1 was 0.981.The indirect response (IDR) model was used to build the relationship model of DPP-4 inhibition ratio and insulin.The parameters of kinl and koutl represented the formation and degradation rate constant of insulin, and were estimated as 32.9 mU·L-1·h-1 and 3.54 h-1,respectively.The maximal stimulation efficacy (Smax) was 1.95, and the 50% stimulation DPP-4 inhibition ratio was 0.929.The shape factor was 1.4.As for the IDR model of insulin and glucose, the parameters of kinG and koutG represented the formation and degradation rate constant of glucose, and were estimated as 2.48 mmol·L-1·h-1 and 0.0992 h-1, respectively.The maximal inhibition efficacy (Imax) was 0.757, and the 50% inhibition concentration of insulin was 9.79 mU/L.The shape factor of this model was 7.95.The good stability and predictive function was found by the bootstrap method and visual predictive check, respectively.Conclusion: In this study, the drug effect of sitagliptin, a DPP-4 inhibitor was investigated via the approach of mechanism-based PK/PD modeling.Exploiting the IDR model, the blood concentration of the drug was well linked with the plasma DPP-4 activity, insulin concentration and blood glucose level, which are the essential intermediate links and biomarkers in the hypoglycemic effect.This study provided a better tool with practical application for predicting the efficacy of other DPP-4 inhibitors.