Figure 3.

Metformin plasma concentration‐time profiles under control and drug–drug interaction conditions using fitted in vivo inhibition constant values for multidrug and toxin extrusion proteins after oral administration of 250 mg metformin and 400 mg cimetidine. For the control condition, the optimized parameters shown in Table  1 for β_kidney value of 0.1 (a), 0.3 (b), 0.5 (c), or 0.8 (d) were used. For drug–drug interaction conditions, the optimized parameters were fixed, but the β_kidney value was not fixed and allowed to change as the renal transport processes became inhibited. The black circles and blue triangles represent the observed plasma concentrations under control and drug–drug interaction conditions, respectively, and the black and blue lines represent the corresponding simulation results; β_kidney = PS_urine/(PS_r,eff+PS_urine).