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).

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".

Project description:Basic PBPK (Physiologically Based PharmacoKinetic) model of Acetaminophen. This is a basic model of Acetaminophen (APAP, Paracetamol) pharmacokinetics in humans. Many of the model parameters (compartment volumes, volumetric flow rates, etc.) are scaled allometrically based on the body weight (BW) raised to the 3/4 power. Because of that, the assigned values of many of the parameters are recalculated at run time and are different than the default values for the particular entity (e.g., the volume of a compartment and the volumetric flow rate between compartments). APAP dose is initially given in grams (APAP_Dose_gram), which is converted to moles via the APAP molecular weight (APAP_MW). APAP quantities throughout the rest of the models are given in moles. The base parameters are for a 70Kg human and a pharmacological oral dose of 1.4 gram of APAP. Metabolism is modelled as a single ODE in the liver compartment and the metabolite does not leave that compartment. This model is loosely based on the model of Wambaugh and Shaw (PLoS Comput Biol. 2010 Apr 22;6(4):e1000756. doi: 10.1371/journal.pcbi.1000756. Pubmed ID: PMID- 20421935) with the following changes: The lung lumen compartment was omitted. A kidney compartment was added. Glomerular Filtration is from the kidney compartment. The APAP dose was changed to 1.4g. The gut adsorption rate constant (KGutabs), tissue partition coefficients and liver metabolism rate constant (CLmetabolism) were fit using the human in vivo data of Critchley (Critchley, J. A., Critchley, L. A. H., Anderson, P. J., and Tomlinson, B. 2005 Journal of clinical pharmacy and therapeutics, 30(2), 179-184). To model the extensive re-adsorption of APAP from the kidney tubules back into the blood the QGfr value is modified. This was done by changing the scaling parameter QGFR_ref value from 0.31 to 0.039, resulting in a decrease in the QGfr value of 8 fold (from 7.2 L/hr to 0.91 L/hr). The parameters in this file are the REFSIM parameters from our publication.

Project description:Nafion byproduct 2 (NBP2; CAS: 749836-20-2; Product #: 6164-3-3J; Lot: 512400; SynQuest Laboratories Alachua, FL, USA) is a polyfluoroalkyl ether sulfonic acid that was recently detected in surface water, drinking water, and human serum samples from monitoring studies in North Carolina, USA. We orally exposed pregnant Sprague-Dawley rats to NBP2 from gestation day (GD) 14–18 (0.1–30 mg/kg/d), GD17-21, and GD8 to postnatal day (PND) 2 (0.3–30 mg/kg/d) to characterize maternal, fetal, and postnatal effects. GD14-18 exposures were also conducted with perfluorooctane sulfonate (PFOS) for comparison to NBP2, as well as data previously published for hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). NBP2 produced stillbirth (30 mg/kg), reduced pup survival shortly after birth (10 mg/kg), and reduced pup body weight (10 mg/kg). Histopathological evaluation identified reduced glycogen stores in newborn pup livers and hepatocyte hypertrophy in maternal livers at ≥ 10 mg/kg. Exposure to NBP2 from GD14-18 reduced maternal serum total T3 and cholesterol concentrations (30 mg/kg). Maternal, fetal, and neonatal liver gene expression was investigated using RT-qPCR pathway arrays, while maternal and fetal livers were also analyzed using TempO-Seq transcriptomic profiling. Overall, there was limited alteration of genes in maternal or F1 livers from NBP2 exposure with significant changes mostly occurring in the top dose group (30 mg/kg) associated with lipid and carbohydrate metabolism. Metabolomic profiling indicated elevated maternal bile acids for NBP2, but not HFPO-DA or PFOS, while all three reduced 3-indolepropionic acid. Maternal and fetal serum and liver NBP2 concentrations were similar to PFOS, but ∼10–30-fold greater than HFPO-DA concentrations at a given maternal oral dose. NBP2 is a developmental toxicant in the rat, producing neonatal mortality, reduced pup body weight, reduced pup liver glycogen, reduced maternal thyroid hormones, and altered maternal and offspring lipid and carbohydrate metabolism similar to other studied PFAS, with oral toxicity for pup loss that is slightly less potent than PFOS but more potent than HFPO-DA.

			Action	DRS
	BIOMD0000001039?filename=Zake2021%20-%20PBPK%20Metformin%20Mice%20IV%20single%20dose-biopax2.owl	Owl
	BIOMD0000001039?filename=Zake2021%20-%20PBPK%20Metformin%20Mice%20IV%20single%20dose-biopax3.owl	Owl
	BIOMD0000001039?filename=Zake2021%20-%20PBPK%20Metformin%20Mice%20IV%20single%20dose-matlab.m	Other
	BIOMD0000001039?filename=Zake2021%20-%20PBPK%20Metformin%20Mice%20IV%20single%20dose-octave.m	Other
	BIOMD0000001039?filename=Zake2021%20-%20PBPK%20Metformin%20Mice%20IV%20single%20dose.cps	Other

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Zake2021 - PBPK model of metformin in mice: single dose intavenous

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

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