Journal of Drug Metabolism & Toxicology
Open Access

Abstract

Pharmacokinetic-Pharmacodynamic Analyses of the Antidiabetic Drug, Nateglinide, in Goto-Kakizaki Rats Based on Pharmacological Mechanism

Akiko Kiriyama*, Shunsuke Kimura and Shugo Yamashita

Background: Quantitative understanding of the Pharmacokinetics (PK) and pharmacological effects/side effects of antidiabetic drugs is important for preventing serious complications. We investigated the PK of nateglinide, a rapid and short-lived insulin release model drug, in type 2 diabetes model rats, analysing the time profiles of plasma insulin and glucose levels. Using PK and Pharmacodynamics (PD) analysis, we quantitatively investigated relationship between nateglinide PK and its PD.

Methods: Nateglinide was administered to rats, and blood samples were subsequently collected for PK, insulin, and glucose analyses. PK and PK-PD model analyses of nateglinide were then performed.

Results: The 3-compartment model exhibited slightly better at low plasma concentrations compared to the 2-compartment model. However, low plasma nateglinide concentrations minimally affected plasma insulin and glucose levels. The change in insulin was almost proportional to the plasma nateglinide concentration, and no hysteresis was observed. In contrast, delayed hysteresis was observed between plasma insulin and glucose concentrations, which may be explained by the insulin resistance of the type 2 diabetes model rat.

Conclusion: The PK/PD model for nateglinide was successfully established based on its pharmacological mechanism. This model will enable the estimation of variations in the effects induced by various PK changes.

Published Date: 2024-07-08; Received Date: 2024-06-07