Kurlovics2021 - Metformin partitioning between plasma and RBC with independent Kin and Kout coefficients
Ontology highlight
ABSTRACT:
SUBMITTER: 
Egils Stalidzans
PROVIDER: BIOMD0000001026 | BioModels | 2024-09-02
REPOSITORIES: BioModels
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Publications
Metformin Transport Rates Between Plasma and Red Blood Cells in Humans.
Kurlovics Janis J Zake Darta Maija DM Zaharenko Linda L Berzins Kristaps K Klovins Janis J Stalidzans Egils E
Clinical pharmacokinetics 20210726 1
<h4>Background</h4>Metformin has been used for the treatment of type 2 diabetes for over 60 years; however, its mechanism of pharmacological action is not fully clear. Different hypotheses exist regarding metformin distribution and redistribution mechanisms between plasma and erythrocytes/red blood cells (RBCs).<h4>Objective</h4>We aimed to test the hypothesis that the metformin distribution between plasma and RBC occurs via concentration difference-driven passive transport and estimated transpo ...[more]
Similar Datasets
Project description:This model is a supplementary material of a manuscript
"Diffusion driven metformin exchange transport rates between plasma and red blood cells"
by Janis Kurlovics, Darta Maija Zake, Linda Zaharenko, Kristaps Berzins, Janis Klovins, Egils Stalidzans
The setting of the model correspond to Fig.2 for the case with a single coefficient for experimental values of average concentration curve.
Parameter estimation can be executed using experimental data file "average_exp_data.txt".
A=B if metformin concentration is 0 at t=0.
2024-09-02 | BIOMD0000001040 | BioModels
Project description: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).
2024-09-02 | BIOMD0000001027 | BioModels
Project description: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, JanisKurlovics, Vitalijs Komasilovs, Egils Stalidzans and Janis Klovins.
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). Also plotting the species result after 0.5 hours will reproduce the literature results.
2024-09-02 | BIOMD0000001039 | BioModels
Project description: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, JanisKurlovics, Vitalijs Komasilovs, Egils Stalidzans and Janis Klovins.
This is a whole-body model representing the pharmacokinetics of metformin in the human body. The model is in the form of Ordinary differential equations and describes metformin concentration in 21 compartments.
The model consists of 21 compartments (“compartments” in COPASI model) describing various tissues or tissue sub-compartments and body fluids of metformin action (venous and arterial plasma, red blood cells, 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 1L, but those are “volumeless” compartments as they are only necessary for the calculation of metformin amount, not concentration.
The model consists of 21 species (“species” in COPASI model) that correspond to the metformin concentrations in the 21 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 35 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 62 global quantities – parameters involved in multiple reactions or necessary for another parameter calculation:
1.Parameters describing peroral metformin dose (Metformin Dose in Lumen in mg).
2.Parameter describing human 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.Parameters involved in the scale-up of the model
•Tissue:plasma partition coefficients (Ktp) that were estimated in the mice model.
•Kidney coefficient that is used for the scale-up of metformin elimination and is involved in the calculation of the rate parameters in the reactions “13.4. KidneyPlasma -> KidneyTissue” and “13.5. KidneyTissue -> KidneyTubular”. This parameter was determined using parameter estimation.
•Intestine coefficient that is involved in the calculation of the intestinal reaction rates of the reactions (03.2. IntestineLumen -> Enterocytes (PMAT OCT3), 03.3. Enterocytes -> IntestineVascular (OCT1), 03.4. IntestineLumen -> IntestineVascular (Saturable), 03.6. IntestineLumen -> Enterocytes (Diffusion) , 03.7. IntestineLumen -> IntestineVascular (Diffusion)). The parmaeters for these reactions are taken from Proctor publication and the intectine coefficient is used for the scale-up from the cell-culture to the human intestine.
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. The current model has 14 events and is set for a multiple-dose regimen for 7-day long twice-daily metformin administration.
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 21 compartments, metformin concentrations in the compartments and reaction fluxes of all the reactions (see “Output Specifications” -> “Plots” to activate or deactivate plots). The time-course also includes multiple "Sliders" that allow to easily change 3 parameters - "Body Weight", "Cardiac Output", "Metformin Dose in Lumen in mg".
2024-09-02 | BIOMD0000001028 | BioModels
Project description: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, JanisKurlovics, Vitalijs Komasilovs, Egils Stalidzans and Janis Klovins.
This is a whole-body model representing the pharmacokinetics of metformin in the human body. The model is in the form of Ordinary differential equations and describes metformin concentration in 21 compartments.
The model consists of 21 compartments (“compartments” in COPASI model) describing various tissues or tissue sub-compartments and body fluids of metformin action (venous and arterial plasma, red blood cells, 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 1L, but those are “volumeless” compartments as they are only necessary for the calculation of metformin amount, not concentration.
The model consists of 21 species (“species” in COPASI model) that correspond to the metformin concentrations in the 21 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 35 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 62 global quantities – parameters involved in multiple reactions or necessary for another parameter calculation:
1.Parameters describing peroral metformin dose (Metformin Dose in Lumen in mg).
2.Parameter describing human 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.Parameters involved in the scale-up of the model
•Tissue:plasma partition coefficients (Ktp) that were estimated in the mice model.
•Kidney coefficient that is used for the scale-up of metformin elimination and is involved in the calculation of the rate parameters in the reactions “13.4. KidneyPlasma -> KidneyTissue” and “13.5. KidneyTissue -> KidneyTubular”. This parameter was determined using parameter estimation.
•Intestine coefficient that is involved in the calculation of the intestinal reaction rates of the reactions (03.2. IntestineLumen -> Enterocytes (PMAT OCT3), 03.3. Enterocytes -> IntestineVascular (OCT1), 03.4. IntestineLumen -> IntestineVascular (Saturable), 03.6. IntestineLumen -> Enterocytes (Diffusion) , 03.7. IntestineLumen -> IntestineVascular (Diffusion)). The parmaeters for these reactions are taken from Proctor publication and the intectine coefficient is used for the scale-up from the cell-culture to the human intestine.
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. The current model has 14 events and is set for a multiple-dose regimen for 7-day long twice-daily metformin administration.
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 21 compartments, metformin concentrations in the compartments and reaction fluxes of all the reactions (see “Output Specifications” -> “Plots” to activate or deactivate plots). The time-course also includes multiple "Sliders" that allow to easily change 3 parameters - "Body Weight", "Cardiac Output", "Metformin Dose in Lumen in mg".
2024-09-02 | BIOMD0000001029 | BioModels
Project description:Metformin is the most popular drug to treat type II diabetes. Besides lowering blood sugar, it is proven to have more beneficial effects, including extending life expectancy. However, the underlying mechanisms remain largely elusive. Here, we systematically studied the proteome thermal stability changes induced by a wide dosage range of metformin in a liver cancer cell line using the proteome integral solubility alteration (PISA) assay. This work provides valuable and unique information about the interactions between proteins and this drug, which is not able to obtain using commonly used abundance-based proteomics. The current results demonstrated that the most acceptable target of metformin responsible for lowering blood glucose levels, complex I, was stabilized only under the high-concentration metformin treatment. Intriguingly, the complex IV subunits were significantly stabilized by low concentrations of (such as 0.2 μM) metformin, indicating that the complex IV may play an important role in the sugar-lowering effect. Moreover, low-dose metformin significantly altered ribosome and histone protein stabilities, correlated with the inhibitive effect of cell proliferation by metformin. We further found that low-concentration metformin impacted mitochondrial cargo transport and vesicle transport, while high-concentration metformin affected cell redox responses and cell membrane protein sorting. Systematic investigation of metformin-induced proteome thermal stability changes provides intriguing insights into the molecular mechanisms of lowering blood sugar and the pleiotropic effects of metformin.
2024-01-11 | PXD039382 | Pride
Project description:We report the effects of metformin treatment on the transcriptome of normal human dermal fibroblasts isolated from foreskin (designated 2DD). We sequenced mRNA from 2 replicates of proliferative (PRO) and 2DD cells treated with two concentrations of metformin (0.5mM and 1.0 mM;5 days exposure). Comparative analyses with PRO transcripts a baseline indicate that fibroblsts exposed to different concentration of metformin result in differnetial transcript profiles.
2018-09-01 | GSE104458 | GEO
Project description:C20 were pre-treated with metformin at specified concentration (5 mM) for 2 h, followed by ZIKV infection at MOI 3. After infection of 1.5 h, cells were washed three times with PBS. Medium containing metformin was again supplemented and maintained during the culture. The total RNA of samples at 16 and 48 h were extracted for RNA-seq analysis. We then performed differential expression analysis using data obtained by RNA-seq of ZIKV infection and metformin treatment (16 h and 48 h).
2023-05-03 | GSE231200 | GEO
Project description:Finally differentiated 3T3-L1 adipocytes are treated with insulin (0 or 100nM)or metformin (0 or 2mM)for 2 and 12 hours to understand insulin and metformin(an anti-diabetic drug commonly applied for Non-Insulin Dependent Diabetes Mellitus)action in adipose tissues.
2013-01-30 | E-BAIR-8 | biostudies-arrayexpress
Project description:Our previous studies in Triple-Negative Breast Cancers (TNBCs) have demonstrated high fatty acid Beta-oxidation (FAO) and Electron Transport Chain (ETC) dependency to activate Src kinase by the Y419 autophosphorylation of Src. Higher doses of metformin have been shown to directly inhibit complex I of ETC. Here, analysis of RNA-seq data upon treatment with high concentration of metformin reveals inhibition of various oncopathways including the Src kinase pathway. Our study identifies a clinically relevant therapeutic approach to better manage poorly-targetable TNBCs.
2024-12-03 | GSE222767 | GEO