Pharmacokinetic/Pharmacodynamic Analysis of Metformin using Different Models in Diabetic Rats
Abstract
Backgroud and study aims: Metformin is believed to be the most widely used hypoglycemic agent in the world. We aimed to investigate the pharmacokinetic/pharmacodynamics properties of metformin in diabetic rats using different pharmacodynamics models, and compare models fitting quality. Methods: Streptozotocin diabetic rats received metformin via oral route and blood samples were collected at the schedule times. Plasma metformin concentration and blood glucose levels were measured. Pharmacokinetic/pharmacodynamic analysis was conducted using nonlinear mixed-effects modeling. Metformin pharmacokinetics was described using a 2-compartmental model with first-order absorption. Five pharmacodynamic models were employed to characterize the hypoglycemic effect of metformin: effect-compartment model (I), indirect response (IDR) model with stimulating the loss of blood glucose (II), IDR model with inhibiting the production of blood glucose (III), combined effect-compartment/IDR model with stimulating the removal of blood glucose (IV) and combined effect-compartment/IDR model with inhibiting the input of blood glucose (V). Akaike's information criterion (AIC) values and goodness-of-fit were applied to estimate the pharmacodynamic model. Results: The Model V provided a more appropriate and good-fitting pharmacodynamic characterization of metformin than the others. All the parameter values were estimated with good precision and model evaluation by visual predictive check suggested that…
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