Metformin pharmacokinetic parameters
| Parameter | Wild Type | Oct1/2 Knockout |
|---|---|---|
| Intravenous dose, mg/kga | 5 | 5 |
| AUC0-t, μg · h/ml | 0.991 | 4.39 |
| AUC0-∞, μg · h/ml | 1.02 | 4.64 |
| C0, μg/ml | 6.25 | 23.5 |
| CL, ml · min−1 · kg−1 | 81.7 | 18.0 |
| Vd,ss, ml/kg | 1840 | 530 |
| T1/2, h | 0.50 | 0.62 |
| Urinary excretion, % doseb | 18 ± 2 | 14 ± 2 |
| Creatinine renal CL, ml/min | 0.09 ± 0.01 | 0.08 ± 0.01 |
| Inulin renal CL, ml/min | 0.12 ± 0.03 | 0.19 ± 0.06 |
| Corrected urinary recovery, % dosec | 49 ± 5 | 29 ± 4 |
| Renal CL/GFR ratio | 4 | 1 |
| Oral dose, mg/kgd | 10, 30, 60, 100, 300 | 10, 30, 60, 100, 300 |
| F, % | 59 ± 11 | 64 ± 4 |
| Tmax, h | 1.4 ± 0.5 | 1.0 ± 0.3 |
↵a Noncompartmental parameters were calculated using mean concentrations in composite PK datasets, so variability and p values were not calculated.
↵b Urinary excretion was measured in a separate set of mice with four metabolic cages each containing three mice per group; mean ± S.E.M. for n = 4 metabolic cages; no statistically significant differences were observed between groups.
↵c Urinary recovery was corrected on the basis of the ratio of nominal-to-observed murine GFR (Bingham and Cummings, 1985). Nominal murine GFR is 0.28 ml/min (Davies and Morris, 1993), and observed GFR was measured by creatinine and inulin renal clearance.
↵d Oral bioavailability and Tmax values are presented as the mean ± S.E.M. of the five oral dose levels; no dose-dependent trends in bioavailability or Tmax were observed in the 10 to 300 mg/kg dose range. Individual bioavailabilities at each dose level were calculated using systemic AUC values based on the mean concentrations in composite intravenous and oral PK datasets (n = 4 mice/group per time point). No statistically significant differences were observed between groups.