Fig 1.
Metformin pharmacokinetics in major compartments of metformin action.
Venous plasma (A), portal vein (B), small intestine (C), liver (D), kidney (E), heart (F), muscle (G), adipose (H), brain (I), feces (J) and urine (K) following a single PO 50 mg/kg dose in mice. The red marks represent the experimental data’s concentration-time profiles with error bars representing standard deviation [1] and the blue lines represent the model simulations.
Fig 2.
Venous plasma (A), small intestine (B), liver (C), and stomach (D) following a single intravenous 50 mg/kg dose in mice. The red marks represent the experimental data’s concentration-time profiles with error bars representing standard deviation [1] and the blue lines represent the model simulations.
Table 1.
Metformin pharmacokinetic parameter comparison of experimental data [1] and model simulations in plasma, portal vein, intestine, liver, kidney heart, muscle, adipose tissues, and brain following a single 50mg/kg PO dose in mice.
Table 2.
Metformin pharmacokinetic parameter comparison of experimental data [1] and model simulations in plasma, intestine, and stomach following a single 50mg/kg intravenous dose in mice.
Table 3.
A comparison of metformin tissue-plasma partition coefficients in various mice tissues calculated using the method from Rogers et al. [14] and estimated in the model using parameter estimation, n.a.–data not available.
Fig 3.
Metformin time-course comparison of experimental data and model simulations for tissues.
Plasma (A) following a single 1000mg PO dose in humans [36] and simulations for plasma (B), red blood cells (C), and urine (D) following a single 500mg PO dose in humans [20]. The red marks represent the experimental data’s concentration-time profiles, where the red error bars represent the standard deviation, and the blue lines represent the model simulations.
Table 4.
Metformin pharmacokinetic parameter comparison of experimental data and model simulations in plasma and red blood cells following a single 500mg PO dose in humans [20] and simulations for plasma following a single 1000mg PO dose in humans [36].
Fig 4.
Metformin pharmacokinetics in plasma—model validation results for 250mg (A) [36], 500mg (B) [37], 750mg (C) [38] and 500mg (D) [39] PO doses in humans.
The red marks represent the experimental data’s concentration-time profiles from four different datasets, the error bars represent standard deviation, and the blue lines represent the model simulations.
Table 5.
Validation results of plasma metformin concentration pharmacokinetic parameters–a comparison of model predictions and experimental results of four different datasets in humans.
Fig 5.
Metformin concentration time-courses in major compartments of metformin action.
Plasma (A), liver (B), kidney (C), intestine (D), muscle (E), brain (F), heart (G), adipose (H), stomach (I), lungs (J), the remainder (K), red blood cells (L)—following a single PO dose of 500mg, 1000mg and 1500mg metformin hydrochloride in humans. The red lines represent the concentration-time profiles of the model simulations of the 500mg dose, the green lines represent model simulations for the 1000mg dose and the blue lines represent model simulations for the 1500mg dose.
Table 6.
Metformin pharmacokinetic parameters for different tissues following a single 500mg, 1000mg, and 1500mg PO dose in humans.
Fig 6.
Distribution of metformin amount over tissues that contain more than 2% of the absorbed amount of metformin at PO dose 500 mg.
Red color curves represent adipose tissues, green–kidney, dark blue- muscle, yellow–intestine, light blue–liver, pink–remainder.
Fig 7.
Metformin concentration time-courses in major compartments of metformin action.
Plasma (A), liver (B), kidney (C), intestine (D), muscle (E), brain (F), heart (G), adipose (H), stomach (I), lungs (J), the remainder (K), red blood cells (L)—following four PO doses of 500mg, 1000mg and 1500mg in humans at 0, 12, 24 and 36h in humans. The red lines represent the concentration-time profiles of the model simulations of the 500mg dose, the green lines represent model simulations for the 1000mg dose and the blue lines represent model simulations for the 1500mg dose.
Table 7.
Metformin pharmacokinetic parameters for different tissues following a twice-daily dosing regimen of 500mg, 1000mg, and 1500mg PO dose in humans.
Fig 8.
Metformin concentrations in A—muscle and plasma at normal muscle volume (28L) and increased muscle volume 48L and B—adipose and plasma at normal adipose volume (15L) and increased adipose volume 75L.
Fig 9.
Schematic representation of a physiologically based pharmacokinetic model for metformin in mice and humans.
V–the reaction rate, S–the concentration of metformin at substrate side, P- the concentration of metformin at product side, Qblood−the flow to a particular compartment, Kt:p—tissue:plasma partition (Kt:p) coefficients, Kd—the non-saturable component of transport, Vmax—the maximal velocity, Km—the Michaelis-Menten constant. Red blood cells (RBC) compartment (dashed line) is used only in the human model.
Fig 10.
Intestine and kidney model structures for permeability rate-limited kinetics.
A: Intestinal structure, where Qintestine−blood flow to the small intestine, ST—saturable transport through paracellular space, AT–active transport, Diffc−diffusion into cells, DiffPC−paracellular diffusion, ATIN−active transport into cells by OCT3 and PAMAT transporters, ATOUT—active transport out of cells by OCT1 transporters; B: Renal structure, where Qkidney−renal blood flow, Qurine−urine flow, GFR—glomerular filtration rate, ATIN−active transport into cells by OCT2 transporters, ATOUT—active transport out of cells by MATE1, MATE2-K and OCT1 transporters.