Table 3.

Observed and simulated AUC, C_max, and CL_r ratios of metformin between control and drug–drug interaction conditions with fitted in vivo Ki value for MATEs at various β_kidney values

βkidney a	Fitted in vivo Ki value for MATEs (μM)	Fold changes from simulations
		AUC (1.47 ± 0.75)16	Cmax (1.72 ± 0.97)16	CLr (0.72 ± 0.32)16
0.1	1.71 ± 0.74	1.40	1.52	0.63
0.3	1.34 ± 0.60	1.39	1.50	0.64
0.5	0.64 ± 0.34	1.42	1.54	0.61
0.8	0.23 ± 0.12	1.42	1.54	0.61

AUC, area under the curve; C_max, the maximum plasma concentration; CLr, renal clearance; Ki, inhibition constant; MATEs, multidrug and toxin extrusion proteins.

^aFor the control condition, the β_kidney value was set to 0.1, 0.3, 0.5, or 0.8, and the optimized parameters shown in Table  1 were used. For the 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.