ABSTRACT: This model is supplementary material of publication "Physiologically based metformin pharmacokinetics model of mice and scale-up to humans for the estimation of concentrations in various tissues"
by Darta Maija Zake, Linda Zaharenko, Janis Kurlovics, Vitalijs Komasilovs, Janis Klovins and Egils Stalidzans.
The model is pre-set for simulation of a single peroral dose.
This is a whole-body model representing the pharmacokinetics of metformin in the mouse body. The model is in the form of ordinary differential equations and describes metformin concentration in 20 compartments.
The model consists of 20 compartments (“Compartments” in COPASI model) describing various tissues or tissue sub-compartments and body fluids of metformin action (venous and arterial plasma, intestine, kidney, heart, fat, muscle, brain, lungs, stomach, liver, portal vein, remainder urine and feces). Body weight and the weight of all compartments is expressed as a volume in mL and for the calculations it is assumed that 1mL = 1g. The volumes of most compartments are calculated as a fraction of the body weight/volume, and the fractions are determined from literature data, the volumes of the stomach lumen and intestine lumen are fixed and do not change depending on the body weight. Similarly, the volume of external urine and feces is set to 1mL, but those are “volumeless” compartments as they are only necessary for the calculation of metformin amount, not concentration.
The model consists of 20 species (“Species” in COPASI model) that correspond to the metformin concentrations in the 20 compartments. The initial concentrations for all the species are 0 nmol/mL as metformin is not produced in the body and can only be detected after dose administration.
The model consists of 33 reactions – they describe the transport processes of metformin in the body. The reactions include local parameters that are involved only in that particular reaction and global parameters – parameters that are used in multiple reactions or are calculated depending on another parameter e.g. scale-up coefficients.
The model consists of 52 global quantities – parameters involved in multiple reactions or necessary for another parameter calculation:
1.Parameters describing metformin dose – either in peroral (Metformin Dose in Lumen in mg) or intravenous (Metformin Dose in Plasma in mg).
2.Parameter describing mice physiology – body weight (in mL), cardiac output, blood flow to different compartments described as Q”compartment_name” (for example Qliver describes blood flow to the liver compartment). Qgfr refers to the glomerular filtration rate.
3.Tissue:plasma partition coefficients (Ktp) that are necessary for the scale-up to humans.
4.Parameters involved in the calculation of metformin amount in mg, these parameters are named mg”Compartment_name” (for example mgLiver describes the metformin amount in mg in the liver tissues).
The time points of dose release are defined as “events” in COPASI and can be changed as necessary.
Time course simulations can be accessed through the section “Time Course” in this section the time duration and intervals can be changed. When time-course simulations are run three plots are created – Metformin amount in the 20 compartments, metformin concentrations in the compartments and reaction fluxes of all the reactions (see “Output Specifications” -> “Plots” to activate or deactivate plots).
Egils Stalidzans 
