Parameter | Mouse | Human | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Mean | n | S.D. | 95% CI | Mean | n | S.D. | 95% CI | |||
Maximal velocity, vmax (pmol × min−1 × mg protein−1) | 17,496 | 11 | 7097 | 12,727 | 22,265 | 14,703 | 11 | 4346 | 11,783 | 17,623 |
Affinity for metformin uptake, KM (µM) | 491 | 11 | 155 | 387 | 595 | 2198 | 11 | 1154 | 1422 | 2973 |
Metformin in vitro clearance, CLin vitro (µl × min−1 × mg protein−1) | 37 | 11 | 16.1 | 26.2 | 47.9 | 7.85 | 11 | 3.9 | 5.23 | 10.5 |
Metformin passive diffusion, CLdiff (µl × min−1 × mg protein−1)a | 0.34 | 11 | 0.20 | 0.21 | 0.48 | 0.34 | 11 | 0.20 | 0.21 | 0.48 |
OCT1 expression in liver, Ein vivo (pmol × mg protein−1) | 1.27 | 20 | 0.72 | 0.93 | 1.61 | 1.44 | 12 | 1.09 | 0.75 | 2.13 |
OCT1 expression in vitro, Ein vitro (pmol × mg protein−1) | 11.3 | 9 | 5.23 | 7.3 | 15.3 | 15.4 | 9 | 4.92 | 11.7 | 19.2 |
Predicted metformin liver-to-blood partition coefficient, Kp,ub | 14.4 | 11 | 4.93 | 11.1 | 17.7 | 3.34 | 11 | 0.98 | 2.68 | 4.0 |
Predicted maximal hepatic metformin concentrations (µM)c | 746 | 11 | 254 | 575 | 659 | 66.9 | 11 | 19.6 | 53.7 | 80.0 |
Observed metformin Kp,ud | 6.8 | 2.5 | ||||||||
Observed maximal hepatic metformin concentrations (µM)d | 350 |
S.D., standard deviation; n, number of independent measurments; CI, confidence interval.
↵a Passive diffusion was estimated based on the uptake in control HEK293 cells transfected with the empty vector pcDNA5 (Supplemental Fig. 2A). Therefore, the values do not differ between mouse and human.
↵b kp,u was calculated as described in Materials and Methods. Liver weights used for the calculations were 1500 g for human and 2.5 g for mouse (Rogers and Dintzis, 2018). The total amount of protein was 90 and 115 mg × g liver−1 for human and mouse liver, respectively (Sohlenius-Sternbeck, 2006).
↵c Hepatic concentrations were calculated assuming portal vein concentrations of 51.7 µM for mouse (Wilcock and Bailey, 1994) and 20 µM for human [double the Cmax observed in humans after 1 g of metformin (Shu et al., 2007; Gormsen et al., 2016)].
↵d The experimental data of mouse kp and hepatic concentrations were obtained from Wilcock and Bailey (1994) 30 min after an oral dose of 50 mg/kg metformin. The concentrations were calculated assuming 2.5 g average weight and 1.3 ml average volume of mouse liver. The human kp was obtained from Gormsen et al. (2016). No experimental data of human liver concentrations were available.