Pharmacokinetic/Pharmacodynamic Analysis of Metformin using Different Models in Diabetic Rats

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 the proposed model is robust. Conclusion: The proposed pharmacokinetic/pharmacodynamic model may be useful in the description for the relationship between metformin concentration and its glucose-lowering effects. For metformin, biophase distribution and inhibiting the production of glucose may be existed simultaneously.