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Physiologically based metformin pharmacokinetics model of mice and scale-up to humans for the estimation of concentrations in various tissues - PubMed

  • ️Fri Jan 01 2021

Randomized Controlled Trial

Physiologically based metformin pharmacokinetics model of mice and scale-up to humans for the estimation of concentrations in various tissues

Darta Maija Zake et al. PLoS One. 2021.

Abstract

Metformin is the primary drug for type 2 diabetes treatment and a promising candidate for other disease treatment. It has significant deviations between individuals in therapy efficiency and pharmacokinetics, leading to the administration of an unnecessary overdose or an insufficient dose. There is a lack of data regarding the concentration-time profiles in various human tissues that limits the understanding of pharmacokinetics and hinders the development of precision therapies for individual patients. The physiologically based pharmacokinetic (PBPK) model developed in this study is based on humans' known physiological parameters (blood flow, tissue volume, and others). The missing tissue-specific pharmacokinetics parameters are estimated by developing a PBPK model of metformin in mice where the concentration time series in various tissues have been measured. Some parameters are adapted from human intestine cell culture experiments. The resulting PBPK model for metformin in humans includes 21 tissues and body fluids compartments and can simulate metformin concentration in the stomach, small intestine, liver, kidney, heart, skeletal muscle adipose, and brain depending on the body weight, dose, and administration regimen. Simulations for humans with a bodyweight of 70kg have been analyzed for doses in the range of 500-1500mg. Most tissues have a half-life (T1/2) similar to plasma (3.7h) except for the liver and intestine with shorter T1/2 and muscle, kidney, and red blood cells that have longer T1/2. The highest maximal concentrations (Cmax) turned out to be in the intestine (absorption process) and kidney (excretion process), followed by the liver. The developed metformin PBPK model for mice does not have a compartment for red blood cells and consists of 20 compartments. The developed human model can be personalized by adapting measurable values (tissue volumes, blood flow) and measuring metformin concentration time-course in blood and urine after a single dose of metformin. The personalized model can be used as a decision support tool for precision therapy development for individuals.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
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
Fig 2. Metformin pharmacokinetics.

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.

Fig 3
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.

Fig 4
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.

Fig 5
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.

Fig 6
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
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.

Fig 8
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
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
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.

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DMZ, JK, VK, and ES are funded by Latvian Council of Science, Grant Number: LZP‐2018/2‐0088.