Abstract

The physiological parameters that describe the reasons behind metformin accumulation in renal failure patients are not fully understood. The effect of high creatinin level in these patients on the elimination of metformin is unknown. The objectives of this work were to (1) evaluate the utility of Physiologically based pharmacokinetic (PBPK) modeling to predict the plasma levels of metformin in healthy and renal impairment individuals (2) identify parameters that explain the observed plasma levels in renal impairment (3) investigate the correlation between creatinine levels and metformin elimination by MATE1 transporter assuming competitive inhibition on this transporter. All simulations were performed using a PBPK approach in GastroPlus™. The simulated data was compared to experimental data in healthy adults and renal failure patients, who received 850 mg metformin HCl. To investigate the effect of creatinin level on the elimination of metformin through MATE1 transporter, 0.35, 0.5, 1, 2, and 5 mg/dl of creatinine on the elimination of 10 µM metformin were investigated in human embryonic kidney (HEK293) and in MATE1 overexpressed HEK293 cell. Our model was able to predict metformin absorption in healthy and renal failure patients. The renal dysfunction model showed that a down-regulation of the MATE1 transporter in kidney and liver was necessary to explain the increase in drug concentration in these patients. However, the accumulation of creatinine in renal impairment patients could not be linked to the MATE1 down-regulation. Understanding the reasons for the increase in metformin blood concentrations can help in reducing the clinical studies and the side effects in these patients.