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Pharmacokinetic-Pharmacodynamic Analyses of Anti-diabetes, Glimepiride: Comparison of the Streptozotocin-Induced Diabetic, GK and Wistar Rats

Akiko Kiriyama, Shunsuke Kimura, Chizuki Banba, Miki Yamakawa, Rie Yajima, Akino Honbo and Katsumi Iga    

Efficacy and safety of a drug and its plasma concentration are closely correlated, and plasma concentrations are used as an index of the drug’s effects. Therefore, it is important to understand the relationship between the drug’s plasma concentration and its effects. Plasma glucose control of diabetics retards its progression and glimepiride is widely used for its treatment. In the present study, pharmacokinetic-pharmacodynamic analysis of glimepiride was performed in Wistar rats, with normal plasma glucose levels (Normal), and streptozotocin-induced type 1 diabetes rats (Type 1) and type 2 diabetes GK rats (Type 2). The PK-PD model was structured to investigate time-dependent plasma glucose changes in relation to the plasma concentration, and the PK and PD characteristics of glimepiride were investigated.

PK analysis of glimepiride in the three groups showed no significant differences in total body Clearance (CL) and half-life of the β phase. Plasma concentration profiles at a 0.5 mg/kg dose increased in the following order; Type 1, Normal, and Type 2 groups. The area under the plasma concentration-time curves for glimepiride was dosedependent in Normal and Type 2 groups. The CL decreased in the Type 2 group compared to the other groups at a 0.5 mg/kg dose. The maximum decrease in the plasma glucose level was increased in the following order; Normal, Type 2, and Type 1.

From the estimated PK-PD analysis, the plasma glimepiride concentration necessary to produce hypoglycemic effects was higher, and the responsiveness of the drug at a drug concentration at the half-maximum effect was quicker, in the Type 2 group compared to the other groups. These effects of glimepiride were considered to improve the pathological condition. This study of the PK-PD characteristics of glimepiride is useful for prediction of the influence of drug-drug interactions and the change in clinical conditions of patients.