@article{APS4308,
author = {Xin-gang Li and Liang Li and Xuan Zhou and Ye Chen and Yu-peng Ren and Tian-yan Zhou and Wei Lu},
title = {Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats},
journal = {Acta Pharmacologica Sinica},
volume = {33},
number = {11},
year = {2016},
keywords = {},
abstract = {Aim: To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats.
Methods: Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutaneous administration of a single dose of exenatide (4.2, 42, or 210 μg/kg), serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insulin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin (in effect compartment) stimulating glucose disposition and insulin (in insulin compartment) inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model program. Visual predictive check and model evaluation were used to make assessments.
Results: Exenatide exhibited rapid absorption with ka=4.45 h-1, and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated Sm1 of 0.822 and SC50 of 4.02 μg/L. It was demonstrated that insulin stimulated glucose dissipation (Sm2=0.0513) and inhibited the production of glucose (Im=0.0381). Visual predictive check and model evaluation study indicated that a credible model was developed.
Conclusion: The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/4308}
}