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二肽基肽酶 (dipeptidyl peptidase-4,DPP-4) 抑制剂通过阻碍某些肠促胰岛素的失活、进而增加胰岛素的分泌来发挥抗高血糖作用.本研究在链脲霉素诱导的2型糖尿病大鼠模型中,使用高效液相色谱法测定单次口服300 mg/kg剂量下DPP-4抑制剂西他列汀的血药浓度,并建立了一级吸收的一室药物动力学 (pharmacokinetic,PK) 模型,用以描述西他列汀在大鼠体内的PK行为,以及预测药效动力学 (pharmacodynamic,PD) 实验中各剂量下的相应血药浓度.随后测定了1、5、10 mg/kg西他列汀给药后糖尿病大鼠DPP-4活性、胰岛素和血糖水平数据,建立基于机制的PK/PD模型.该模型以希尔氏方程表示西他列汀对DPP-4活性的抑制作用,用间接效应模型描述胰岛素和血糖的变化过程.综上所述,该模型阐释了西他列汀抗高血糖的作用机制,还可以外推应用于其他物种或其他DPP-4抑制剂.“,”Dipeptidyl peptidase-4 (DPP-4) inhibitors exert their antihyperglycemic effects through repressing inactivation of certain incretin hormones and thus increasing insulin secretion and controlling glucose level. In this study, the plasma concentrations of sitagliptin, a potent DPP-4 inhibitor, after a single oral dose of 300 mg/kg in streptozotocin-induced type 2 diabetic rats were determined by HPLC. A one-compartment pharmacokinetic (PK) model with first order absorption was developed to describe the PK profile of sitagliptin, and the drug concentrations at the doses given in the pharmacodynamic (PD) study were simulated accordingly. The dynamic changes in DPP-4 activity, insulin concentration and blood glucose level in diabetic rats at doses of 1, 5 and 10 mg/kg were measured, and a mechanism-based PK/PD model was established subsequently. In this model, the inhibitory effect of sitagliptin on DPP-4 activity was demonstrated using the Hill's function with direct link, and the downstream increase in insulin secretion and inhibition of glucose production were characterized using indirect response (IDR) models. This model interpreted the mechanism of antihyperglycemic action of sitagliptin, and may be modified and applied to other species or other agents in this class.