Human body nitrite physiological toxicokinetic model and construction method thereof

Abstract

The invention discloses a human nitrite physiological toxicokinetic model and a construction method thereof. The construction method comprises the following steps: determining atrioventricular division of a human tissue structure, constructing a model of each atrioventricular and determining model parameters of each atrioventricular; the human body division atrioventricle comprises a central chamber, a rapid perfusion atrioventricle, a slow perfusion atrioventricle and a gastrointestinal tract absorption module; constructing a human body nitrite physiological toxicokinetic model by establishing a differential equation of nitrite dynamic behaviors of each atrioventricle; the nitrite dynamic behaviors comprise absorption, distribution, metabolism and excretion processes; receiving individualized parameters input by a user; assigning values to human physiology and anatomy parameters, and setting an initial condition, a time step length and a simulation duration of the model; therefore, the human body nitrite physiological toxicokinetic model can be simulated to generate a nitrite concentration-time curve of each atrioventricle. According to the invention, the accuracy of simulating dynamic change of nitrite in vivo can be improved.

Description

Technical Field

[0001] This application relates to the fields of food safety and environmental science and technology, and in particular to a physiological toxicokinetics model of human nitrite and its construction method. Background Technology

[0002] Nitrites are common chemical substances widely found in food, water, and the environment. In the food industry, nitrites are often used as preservatives and colorants, especially in the curing and processing of meats. However, nitrites may be toxic to humans, particularly at high concentrations. Nitrites can react with amines in the gastrointestinal tract to form nitrosamines, known carcinogens linked to various cancers, including stomach and esophageal cancer. Furthermore, nitrites may affect oxygen transport in the blood, leading to methemoglobinemia, particularly pronounced in children and pregnant women. Therefore, accurately assessing the dynamic behavior and potential toxicity of nitrites in the human body is crucial for food safety, public health, and clinical medicine.

[0003] Traditional nitrite toxicokinetics studies primarily rely on conventional one-compartment / two-compartment models and animal experimental data. However, these methods have significant limitations, failing to comprehensively and accurately simulate the dynamic behavior and potential toxicity of nitrite in the human body. Existing methods have the following limitations:

[0004] (1) Although the traditional one-compartment / two-compartment model is widely used in pharmacokinetic studies, it cannot quantify the accumulation effect of nitrite in tissues such as the brain and heart.

[0005] (2) The existing model is a single clearance pathway and does not integrate the dynamic competition between oxidative metabolism and renal excretion.

[0006] (3) Lack of individualized interface, unable to adapt to changes in physiological state (such as increased blood flow during exercise) or population differences (such as weight differences between children and adults). Summary of the Invention

[0007] Based on this, and in response to the aforementioned technical problems, a physiological toxicokinetics model of human nitrite and its construction method are provided to solve the problem that existing models are not accurate enough in simulating the dynamic changes of nitrite in the body.

[0008] Firstly, a method for constructing a physiological toxicokinetics model of human nitrite, the method comprising:

[0009] The human body is divided into compartments, and a model of each compartment is constructed, along with the model parameters for each compartment. The compartments include: a central compartment, a rapid perfusion compartment, a slow perfusion compartment, and a gastrointestinal absorption module. The central compartment contains the circulatory system; the rapid perfusion compartments include the liver, kidneys, brain, and heart; the slow perfusion compartments include muscles, fat, skin, and bones; and the gastrointestinal module includes the stomach and small intestine.

[0010] A physiological toxicokinetic model of nitrite in the human body is constructed by establishing differential equations for the dynamic behavior of nitrite in each compartment; the dynamic behavior of nitrite includes: absorption, distribution, metabolism and excretion processes; the clearance process integrates the oxidative metabolism of nitrite and renal excretion, and establishes a two-way dynamic differential equation.

[0011] Receive personalized parameters input by the user;

[0012] The physiological and anatomical parameters of the human body are assigned values, and the initial conditions, time step, and simulation duration of the model are set so that the human nitrite physiological toxicokinetics model can be simulated to generate nitrite concentration-time curves for each compartment.

[0013] Optionally, in the above scheme, the individualized parameters include: physiological parameters, nitrite physicochemical parameters, and kinetic parameters;

[0014] The human physiological and anatomical parameters include tissue and organ volume, blood flow; physicochemical parameters; and kinetic parameters. The physicochemical parameters include the tissue-plasma partition coefficient, and the kinetic parameters include the rates of chemical absorption, metabolism, and excretion.

[0015] In the above scheme, optionally, the volume of the tissue or organ is determined by the following formula: Tissue or organ volume = body weight × organ weight as a percentage of body weight / organ density;

[0016] The tissue-plasma partition coefficient = peak tissue concentration / peak plasma concentration.

[0017] Optionally, in the above scheme, the absorption process includes gastric emptying and small intestinal absorption:

[0018] The kinetic equation for gastric emptying is as follows:

[0019]

[0020]

[0021] Where dA_stomach / dt: the rate of change of nitrite in the stomach over time (mg / h), stomach_emptying: the rate of gastric emptying (mg / h). Maximum gastric emptying rate (mg / h) Half-maximal gastric emptying inhibition (mg), A_stomach: amount of nitrite in the stomach (mg), Δt: time step (h), stomach_dose: amount of nitrite actually entering the gastric cavity after each nitrite intake (mg).

[0022] The kinetic equation for small intestinal absorption is as follows:

[0023] si_inflow=stomach_emptying

[0024]

[0025]

[0026] Among them, dA_ si / dt: Rate of change of nitrite in the small intestine over time (mg / h), si_inflow: Small intestinal inflow rate (mg / h), si_outflow: Small intestinal outflow rate (mg / h), k_abs: Small intestinal absorption rate constant (h). -1 ), A_ si : Nitrite levels in the small intestine (mg).

[0027] Optionally, in the above scheme, the metabolic process is a first-pass metabolism in the liver; the first-pass metabolism in the liver includes the amount of nitrite entering and leaving the liver through the portal vein, and the metabolic rate in the liver;

[0028] The portal vein concentration:

[0029]

[0030] Where Q_liver: liver blood flow rate (L / h), C_portal: portal vein nitrite concentration (mg / L);

[0031] The kinetic equations for the input and output of nitrite are as follows:

[0032] liver_inflow=Q_liver×C_portal

[0033]

[0034] Wherein, liver_inflow: liver inflow rate (mg / h), liver_outflow: liver outflow rate (mg / h), V_liver: liver volume (L), A_liver: amount of nitrite in the liver (mg), P_liver: liver-plasma partition coefficient;

[0035] The kinetic equation for the metabolic rate is:

[0036]

[0037]

[0038] Wherein, dA_liver / dt: the rate of change of nitrite content in the liver over time (mg / h), and metabolic_rate: the metabolic rate (mg / h). Maximum metabolic rate (mg / h) Michaelis constant (mg / L), C_liver: nitrite concentration in the liver (mg / L), A_liver: nitrite content in the liver (mg).

[0039] Optionally, in the above scheme, the distribution process includes a tissue distribution process and a blood distribution process;

[0040] The kinetic equation for the distribution of the tissue is as follows:

[0041]

[0042] Where dA_organ / dt: rate of change of nitrite in tissue over time (mg / h), Q_organ: tissue blood flow rate (L / h), V_organ: tissue volume (L), P_organ: tissue-plasma partition coefficient, A_organ: amount of nitrite in tissue (mg), C_blood: nitrite concentration in blood (mg / L), δ: δ=10 -6 , to prevent the zero threshold (L);

[0043] The kinetic equation for the distribution in the blood is as follows:

[0044]

[0045] Wherein, dA_blood / dt: the rate of change of nitrite in blood over time (mg / h), and A_blood: the amount of nitrite in blood (mg).

[0046] Optionally, in the above scheme, the kinetic equation for renal excretion is:

[0047] kidney_inflow=Q_kidney×C_blood

[0048]

[0049]

[0050]

[0051] Wherein, kidney_inflow: renal inflow rate (mg / h), kidney_outflow: renal outflow rate (mg / h), dA_kidney / dt: rate of change of nitrite in the kidney over time (mg / h), renal_clearance: renal clearance rate (mg / h), Q_kidney: renal blood flow rate (L / h), V_kidney: kidney volume (L), P_kidney: kidney-plasma partition coefficient, CL_renal: renal clearance rate (L / h), and A_kidney: amount of nitrite in the kidney (mg);

[0052] The kinetic equation for the nitrite oxidation metabolism is as follows:

[0053]

[0054] Where, metabolic_rate: metabolic rate (mg / h), Maximum metabolic rate (mg / h) Michaelis constant (mg / L), C_liver: nitrite concentration in liver (mg / L), V_liver: nitrite amount in liver (mg);

[0055] The dynamic differential equation for renal clearance of nitrite is:

[0056]

[0057] Wherein, renal_clearance: renal clearance rate (mg / h), V_kidney: kidney volume (L), CL_renal: renal clearance rate (L / h), and A_kidney: amount of nitrite in the kidney (mg).

[0058] In the above scheme, optionally, the initial conditions of the model are that the nitrite content in each compartment is 0, the daily intake of nitrite is 0.79 mg, the time step is 0.01 h, and the simulation duration is 24 h.

[0059] Secondly, a physiological toxicokinetic model of nitrite was constructed using the method described in the first aspect above.

[0060] This application has at least the following beneficial effects:

[0061] This application can achieve the following:

[0062] (1) Calculate the internal tissue nitrite dose based on the given exposure scenario, and then analyze the reaction mechanism based on the internal tissue dose.

[0063] (2) To study susceptibility to individual physiological parameters during life stages, some physiological and biochemical parameters in the model are based on empirical data that change over time, and can be used to simulate the tissue concentration distribution of nitrite during the life cycle. For example, organ volume is obtained by multiplying body weight and the percentage of organ weight to body weight by organ density;

[0064] (3) Provides modeling tools for extrapolating nitrite doses from in vitro to in vivo and for assessing health risks.

[0065] Therefore, by constructing compartmentalized structures, the accumulation effects in tissues such as the brain and heart can be quantified. Simultaneously, the oxidative metabolism and renal excretion pathways of nitrite were constructed, and a dynamic differential equation was established with dynamic allocation coefficients that are dynamically adjusted under different physiological states, thereby improving the accuracy of simulating the dynamic changes of nitrite in the body. A user input interface was included to accept user-input data, adapting to different population groups. Attached Figure Description

[0066] Figure 1 A flowchart illustrating a method for constructing a physiological toxicokinetic model of human nitrite is provided in one embodiment of this application;

[0067] Figure 2 A schematic diagram of a physical model for constructing a physiological toxicokinetics model of human nitrite is provided in one embodiment of this application;

[0068] Figure 3 This application provides an embodiment of the curves showing the change of nitrite concentration in various tissues over time, generated using a human nitrite physiological toxicokinetics model.

[0069] Figure 4 This application provides a curve showing the change of nitrite levels in various tissues over time, generated using a human nitrite physiological toxicokinetics model, as an embodiment of the present application.

[0070] Figure 5 The curves showing the change of nitrite concentration over time in the stomach, small intestine, liver, kidney, brain, heart, fat, and blood, generated using a human nitrite physiological toxicokinetics model, are provided in one embodiment of this application.

[0071] Figure 6 The curves showing the change of nitrite levels in the stomach, small intestine, liver, kidney, brain, heart, fat, and blood over time, generated using a human nitrite physiological toxicokinetic model, are provided as an embodiment of this application. Detailed Implementation

[0072] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application.

[0073] In one embodiment, such as Figure 1 As shown, a method for constructing a physiological toxicokinetic model of human nitrite is provided: the method includes:

[0074] Step S1: Determine the compartmentalization of human tissue structure and construct a model of each compartment, as well as determine the model parameters of each compartment; the human body compartmentalization includes: central compartment, rapid perfusion compartment, slow perfusion compartment, and gastrointestinal absorption module; the central compartment contains the circulatory system; the rapid perfusion compartment includes the liver, kidneys, brain, and heart; the slow perfusion compartment includes muscles, fat, skin, and bones; and the gastrointestinal module includes the stomach and small intestine.

[0075] The room division in step S1 includes:

[0076] Central compartment (blood): Serves as the hub for nitrite distribution, connecting the compartments of various organs.

[0077] Rapidly perfused chambers (tissues that are rapidly perfused): including the liver, kidneys, brain, and heart, with high blood flow rates (Q≥50L / h) and rapid distribution of nitrite.

[0078] Slow chambers (slowly perfused tissues): including fat, etc., with low blood flow rate (Q≤10L / h) and delayed nitrite accumulation.

[0079] Gastrointestinal module: stomach and small intestine, simulating the absorption process of nitrite after oral ingestion.

[0080] Step S2: A physiological toxicokinetic model of human nitrite is constructed by establishing differential equations for the dynamic behavior of nitrite in each compartment. The dynamic behavior of nitrite includes absorption, distribution, metabolism, and excretion. The clearance process integrates the oxidative metabolism of nitrite and renal excretion, and a two-way dynamic differential equation is established. This integrates the oxidative metabolism of nitrite (mediated by CYP2E1 enzyme) and renal excretion (glomerular filtration), and establishes a dynamic differential equation representing the competitive relationship between the two channels.

[0081] Step S3: Receive the personalized parameters input by the user.

[0082] In step S3, the model is set with an individualized parameter interface, which supports users to input physiological parameters (such as blood flow, organ volume, creatinine clearance rate) to adapt to different populations.

[0083] Step S4: Assign values ​​to the human physiological and anatomical parameters, and set the initial conditions, time step, and simulation duration of the model; so that the human nitrite physiological toxicokinetics model can be simulated and generate nitrite concentration-time curves for each compartment.

[0084] In the above-mentioned method for constructing a human nitrite physiological toxicokinetics model, the constructed human nitrite physiological toxicokinetics model can achieve:

[0085] (1) Calculate the internal tissue nitrite dose based on the given exposure scenario, and then analyze the reaction mechanism based on the internal tissue dose.

[0086] (2) To study susceptibility to individual physiological parameters during life stages, some physiological and biochemical parameters in the model are based on empirical data that change over time, and can be used to simulate the tissue concentration distribution of nitrite during the life cycle. For example, organ volume is obtained by multiplying body weight and the percentage of organ weight to body weight by organ density;

[0087] (3) Provides modeling tools for extrapolating nitrite doses from in vitro to in vivo and for assessing health risks.

[0088] Therefore, by constructing compartmentalized structures, the accumulation effects in tissues such as the brain and heart can be quantified. Simultaneously, the oxidative metabolism and renal excretion pathways of nitrite were constructed, and a dynamic differential equation was established with dynamic allocation coefficients that are dynamically adjusted under different physiological states, thereby improving the accuracy of simulating the dynamic changes of nitrite in the body. A user input interface was included to accept user-input data, adapting to different population groups.

[0089] In one embodiment, the individualized parameters include: physiological parameters, nitrite physicochemical parameters, and kinetic parameters;

[0090] The human physiological and anatomical parameters include tissue and organ volume, blood flow; physicochemical parameters; and kinetic parameters. The physicochemical parameters include the tissue-plasma partition coefficient; and the kinetic parameters include the rates of chemical absorption, metabolism, and excretion. Dynamic partition coefficient: The tissue / plasma partition coefficient (Kp) is defined as a blood flow-dependent parameter that dynamically adjusts with changes in organ blood flow.

[0091] In this embodiment, organ volume: a standard reference individual with a height of 170cm and a weight of 63kg was selected. The volume of each organ is expressed as a percentage of body weight (%BW) or absolute volume, and converted into the required volume (L) for modeling based on tissue density. Key parameters are as follows:

[0092] According to the formula: Organ volume = Body weight × Organ weight as a percentage of body weight / Organ density (the density of most internal organs is approximately 1.00 g / cm³). 3Adipose tissue density: 0.916 g / cm³ 3 Bone marrow-abstem tissue density: 1.92 g / cm³ 3 wait).

[0093] Adipose tissue: mass 12500g, volume 12500g ÷ 0.916g / cm³ 3 =13.65L.

[0094] Blood: Blood accounts for 7.5% of the total volume, with a mass of 63000g × 7.5% = 4725g. Based on a density of 1.05g / cm³... 3 Calculate the volume as 4725g ÷ 1.05g / cm³. 3 =4.50L.

[0095] Brain: Weight 1460g, density 1.00g / cm³ 3 Calculate the volume as 1.46 kg ÷ 1.00 g / cm³. 3 =1.46L.

[0096] Stomach: Weight 145g, density 1.05g / cm³ 3 (Approximately the wet density of gastrointestinal tissue), volume = 145g ÷ 1.05g / cm³ 3 =0.138L.

[0097] Small intestine: weight 612g, density 1.04g / cm³ 3 (Including mucus and intestinal wall tissue), volume = 612g ÷ 1.04g / cm³ 3 / L=0.59L.

[0098] Heart: Mass 325g, Volume 325g ÷ 1.00g / cm³ 3 =0.325L.

[0099] Kidney: Weight 290g, volume 290g ÷ 1.00g / cm³ 3 =0.29L.

[0100] Liver: Weight 1410g, volume 1410g ÷ 1.00g / cm³ 3 =1.41L.

[0101] The volume parameters of various human organs are shown in Table 1:

[0102] Table 1

[0103] Parameter name Symbol abbreviation unit Parameter value blood volume V_blood L 4.5 stomach volume V_stomach L 0.138 Small intestine volume V_small intestine L 0.59 liver volume V_liver L 1.41 kidney volume V_kidney L 0.29 brain volume V_brain L 1.46 Heart volume V_heart L 0.325 fat volume V_fat L 13.65

[0104] Toxicokinetic parameters: Based on the study by Martinez AM, Mancha F, Gomes A, et al., the immediate-release (IR) formulation is: ka = 4.5 ± 2.0 h. -1 The plasma concentration fitting results of IR capsules from the literature reflect the rapid gastrointestinal absorption characteristics. Enteric-coated (EC) formulation: ka = 1.55 ± 0.01 h -1 The results were obtained by correcting for the lag time (2.1 h) by combining the delayed release mechanism of enteric coating.

[0105] The elimination rate was taken as the average of the IR and EC formulations (ke = 1.37-1.38 h). -1 (This includes the first-pass metabolism in the liver plus ongoing metabolism) and renal excretion. Renal clearance (CL_renal) was estimated at 7.5 L / h using similar nitrite data from the TOXNET database.

[0106] Based on intravenous injection data from Dejam et al. (2007), the Michaelis constant K_m_met is 65 μM, and K_m_met (mg / L) = Km (μM) × MW / 1000 = 3 mg / h.

[0107] refer to et al. (2006), gastric emptying half-life of liquid: 10-20 min.

[0108] Liquid evacuation half-life T 50 =T = median value of 15-20 min: 50 =17.5min=0.292h.

[0109] According to dA / dt=-k×A, T 50 =ln2 / k,k=0.693 / 0.292=2.37h -1 .

[0110] refer to According to et al. (2006), the maximum gastric emptying rate in the human body is 10-20 mL / min. Taking the median value of 15 mL / min = 0.9 L / h.

[0111] Based on the gastric contents concentration in the patented scenario, the nitrite intake is 0.79 mg.

[0112] Stomach contents volume: 265.9g of vegetables ingested, with a vegetable density of ≈0.8g / mL, and a volume of ≈0.332L.

[0113] The postprandial gastric distension volume is approximately 0.8-1.5L, so we take 0.8L.

[0114] Nitrite concentration: C = 0.79 mg × 0.8 L = 0.9875 mg / L.

[0115] V_max_empt = (volume emptying rate) × C = 0.9 L / h × 0.9875 mg / L = 0.889 mg / h.

[0116] K_m_empt=V_max_empt / k=0.889 / 2.37=0.374 mg.

[0117] The maximum metabolic rate of the liver (V_max_met) was calculated using enzyme kinetics theory: based on Shimada et al. (2004) the total amount of cytochrome P450 enzyme in human liver (approximately 90 nmol), and based on Houston & Galetin (2008) the typical turnover number (k_cat = 20 h). - 1) The theoretical maximum metabolic rate was found to be 1800 nmol / h; converted to mass rate using sodium nitrite (NaNO2, molecular weight 69 g / mol): 1800 nmol / h × 69 ng / nmol = 0.124 mg / h. Considering enzyme specificity, liver physiological limitations, and enzyme-specific inhibition, the rate is calculated at 50% activity as 0.2 mg / h.

[0118] The dynamic parameters are shown in Table 2:

[0119] Table 2

[0120] Parameter name Symbol abbreviation unit Parameter value Renal clearance rate CLrenal L / h 7.5 Small intestinal absorption rate constant Kabs h-1 0.5 Michaelis constant K_m_met mg / L 3 Maximum evacuation rate V_max_empt L / h 0.889 Maximum metabolic rate V_max_met mg / h 0.2 Half of the gastric emptying inhibition K_m_empt mg 0.374

[0121] The plasma partition coefficients for various organs and tissues in the human body are calculated using a simplified method based on peak concentration (Cmax): P = Tissue peak concentration (Cmax) / Plasma peak concentration (Cmax). This method is suitable for substances that rapidly reach distribution equilibrium, and the data is derived from PK-Sim simulation results. Table 3 shows the plasma partition coefficients for various tissues and organs in the human body based on the PK-Sim simulation results.

[0122] Table 3

[0123]

[0124]

[0125] The blood flow rate of each organ can be calculated based on the cardiac output rate of 336 L / h and the proportion of blood flow to each tissue and organ. The formula is: Q_organ = cardiac output rate × proportion of blood flow.

[0126] Liver: 336 L / h × 25.5% = 85.68 L / h; Kidney: 336 L / h × 19% = 63.84 L / h;

[0127] Brain: 336 L / h × 12% = 40.32 L / h; Heart: 336 L / h × 4.0% = 13.44 L / h;

[0128] Fat: 336 L / h × 5.0% = 16.8 L / h. See Table 4 for blood flow rates in various organs of the human body.

[0129] Table 4

[0130] Parameter name Symbol abbreviation unit Parameter value Cardiac output rate Q cardiac L / h 336 liver blood flow rate Q liver L / h 85.68 Renal blood flow rate Q kidney L / h 63.84 Cerebral blood flow rate Q brain L / h 40.32 Cardiac blood flow rate Q heart L / h 13.44 Fat blood flow rate Q fat L / h 16.8

[0131] Definition of cardiac blood flow: refers only to blood flow in the coronary arteries (supplying blood to the myocardium), excluding blood within the heart chambers (blood in the heart chambers belongs to the circulatory pool).

[0132] The parameters in this application include:

[0133] Physiological and physicochemical parameters: organ volume, blood flow, derived from (GBZ / T200.1—2007) and (GBZ / T200.2—2007);

[0134] Dynamic allocation coefficient (P): dynamically adjusted according to organ blood flow fluctuations, derived from PK-sim software simulation.

[0135] In one embodiment, the absorption process includes gastric emptying and small intestinal absorption:

[0136] The kinetic equation for gastric emptying is as follows:

[0137]

[0138]

[0139] Where dA_stomach / dt: the rate of change of nitrite in the stomach over time (mg / h), stomach_emptying: the rate of gastric emptying (mg / h). Maximum gastric emptying rate (mg / h) Half-maximal gastric emptying inhibition (mg), A_stomach: amount of nitrite in the stomach (mg), Δt: time step (h), stomach_dose: amount of nitrite actually entering the gastric cavity after each nitrite intake (mg).

[0140] The kinetic equation for small intestinal absorption is as follows:

[0141] si_inflow=stomach_emptying

[0142]

[0143]

[0144] Among them, dA_ si / dt: Rate of change of nitrite in the small intestine over time (mg / h), si_inflow: Small intestinal inflow rate (mg / h), si_outflow: Small intestinal outflow rate (mg / h), k_abs: Small intestinal absorption rate constant (h). -1 ), A_ si : Nitrite levels in the small intestine (mg).

[0145] In one embodiment, the metabolic process is a first-pass metabolism in the liver; the metabolic process is a first-pass metabolism in the liver; the first-pass metabolism in the liver includes the amount of nitrite entering and leaving the liver via the portal vein, and the rate of metabolism in the liver;

[0146] The portal vein concentration:

[0147]

[0148] Where Q_liver: liver blood flow rate (L / h), C_portal: portal vein nitrite concentration (mg / L);

[0149] The kinetic equations for the input and output of nitrite are as follows:

[0150] liver_inflow=Q_liver×C_portal

[0151]

[0152] Wherein, liver_inflow: liver inflow rate (mg / h), liver_outflow: liver outflow rate (mg / h), V_liver: liver volume (L), A_liver: amount of nitrite in the liver (mg), and P_liver: liver-plasma partition coefficient.

[0153] The kinetic equation for the metabolic rate is:

[0154]

[0155]

[0156] Wherein, dA_liver / dt: the rate of change of nitrite content in the liver over time (mg / h).

[0157] metabolic_rate: metabolic rate (mg / h) Maximum metabolic rate (mg / h) Michaelis constant (mg / L), C_liver: nitrite concentration in the liver (mg / L), A_liver: nitrite content in the liver (mg).

[0158] In one embodiment, the distribution process includes a tissue distribution process and a blood distribution process;

[0159] Based on the principle of blood flow velocity limitation, the dynamic equation of organ distribution process is:

[0160]

[0161] Where dA_organ / dt: rate of change of nitrite in tissue over time (mg / h), Q_organ: tissue blood flow rate (L / h), V_organ: tissue volume (L), P_organ: tissue-plasma partition coefficient, A_organ: amount of nitrite in tissue (mg), C_blood: nitrite concentration in blood (mg / L), δ: δ=10 -6 , to prevent the zero threshold (L);

[0162] The kinetic equation for the distribution in the blood is as follows:

[0163]

[0164] Wherein, dA_blood / dt: the rate of change of nitrite in blood over time (mg / h), and A_blood: the amount of nitrite in blood (mg).

[0165] In one embodiment, the kinetic equation for renal excretion is:

[0166] kidney_inflow=Q_kidney×C_blood

[0167]

[0168]

[0169]

[0170] Wherein, kidney_inflow: renal inflow rate (mg / h), kidney_outflow: renal outflow rate (mg / h), dA_kidney / dt: rate of change of nitrite in the kidney over time (mg / h), renal_clearance: renal clearance rate (mg / h), Q_kidney: renal blood flow rate (L / h), V_kidney: kidney volume (L), P_kidney: kidney-plasma partition coefficient, CL_renal: renal clearance rate (L / h), and A_kidney: amount of nitrite in the kidney (mg).

[0171] The kinetic equation for the nitrite oxidation metabolism is as follows:

[0172]

[0173] Where, metabolic_rate: metabolic rate (mg / h), Maximum metabolic rate (mg / h) Michaelis constant (mg / L), C_liver: nitrite concentration in liver (mg / L), V_liver: nitrite amount in liver (mg);

[0174] The dynamic differential equation for renal clearance of nitrite is:

[0175]

[0176] Wherein, renal_clearance: renal clearance rate (mg / h), V_kidney: kidney volume (L), CL_renal: renal clearance rate (L / h), and A_kidney: amount of nitrite in the kidney (mg).

[0177] In one embodiment, the initial conditions of the model are: the initial concentration of each compartment is 0, and the single intake of nitrite is set to 0.79 mg; the time step is 0.01 h to ensure simulation accuracy; the simulation duration is 24 h to cover the complete metabolic cycle of nitrite.

[0178] In one embodiment, some preferred scopes and reasons for this application are as follows:

[0179] (1) Dual-channel clearing percentage:

[0180] Oxidative metabolism: preferably 60%-70% (when the dose is ≤100mg), because metabolism is dominant before the activity of CYP2E1 enzyme is saturated;

[0181] Renal excretion: preferably 20%-50% (dose-dependent), because at high doses (>200mg), metabolic enzymes are saturated, and the proportion of renal excretion increases.

[0182] (2) Range of dynamic allocation coefficients:

[0183] Adipose tissue P_fat = 0.3-1.75, because: blood flow is low at rest (Q_fat = 5L / h), and increased blood flow during exercise leads to an increased tissue-plasma partition coefficient;

[0184] The liver P_liver = 2.5-57.95, based on the liver's high perfusion (Q_liver = 90 L / h) and high metabolic activity.

[0185] In one embodiment, the daily intake of cabbage by consumers was determined to be 265.9g through surveys and experiments. Using the maximum nitrite content variation in cabbage (0.79mg / kg) as the experimental maximum, the PBTK model for the nitrite metabolism process within 24 hours was calculated as follows:

[0186] Initial conditions:

[0187] STARTTIME(starttime(h)) = 0;

[0188] STOPTIME (end time (simulated day)) = 24;

[0189] DT (time step (0.01h)) = 0.01;

[0190] (Oral ingestion of nitrite):

[0191] INITA_stomach = 0; Initial nitrite level in the stomach (mg);

[0192] INITA_small_intestine = 0; Initial nitrite levels in the small intestine (mg);

[0193] INITA_liver = 0; Initial nitrite level in the liver (mg);

[0194] INITA_kidney = 0; Initial renal nitrite level (mg);

[0195] INITA_blood = 0; Initial nitrite levels in the circulatory system (mg);

[0196] INITA_brain = 0; Initial nitrite levels in brain tissue (mg);

[0197] INITA_heart = 0; Initial nitrite content in heart tissue (mg);

[0198] INITA_fat = 0; Initial nitrite content in adipose tissue (mg);

[0199] like Figures 1-6 The model prediction process and results.

[0200] In one embodiment, a human nitrite physiological toxicokinetics model is constructed using the method described above.

[0201] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0202] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A method for constructing a physiological toxicokinetic model of human nitrite, characterized in that, The method includes: The human body is divided into compartments, and a model of each compartment is constructed, along with the model parameters for each compartment. The compartments include: a central compartment, a rapid perfusion compartment, a slow perfusion compartment, and a gastrointestinal absorption module. The central compartment contains the circulatory system; the rapid perfusion compartments include the liver, kidneys, brain, and heart; the slow perfusion compartments include muscles, fat, skin, and bones; and the gastrointestinal module includes the stomach and small intestine. A physiological toxicokinetic model of nitrite in the human body is constructed by establishing differential equations for the dynamic behavior of nitrite in each compartment; the dynamic behavior of nitrite includes: absorption, distribution, metabolism and excretion processes; the clearance process integrates the oxidative metabolism of nitrite and renal excretion, and establishes a two-way dynamic differential equation. Receive personalized parameters input by the user; The physiological and anatomical parameters of the human body are assigned values, and the initial conditions, time step, and simulation duration of the model are set so that the human nitrite physiological toxicokinetics model can be simulated to generate nitrite concentration-time curves for each compartment.

2. The method for constructing the human nitrite physiological toxicokinetics model according to claim 1, characterized in that, The individualized parameters include: physiological parameters, nitrite physicochemical parameters, and kinetic parameters; The human physiological and anatomical parameters include tissue and organ volume, blood flow; physicochemical parameters; and kinetic parameters. The physicochemical parameters include the tissue-plasma partition coefficient, and the kinetic parameters include the rates of chemical absorption, metabolism, and excretion.

3. The method for constructing the human nitrite physiological toxicokinetics model according to claim 2, characterized in that, The volume of the tissue or organ is determined by the following formula: Tissue / Organ Volume = Body Weight × Percentage of Organ Weight to Body Weight / Organ Density; The tissue-plasma partition coefficient = peak tissue concentration / peak plasma concentration.

4. The method for constructing the human nitrite physiological toxicokinetics model according to claim 1, characterized in that, The absorption process includes gastric emptying and small intestinal absorption: The kinetic equation for gastric emptying is as follows: Where dA_stomach / dt: the rate of change of nitrite in the stomach over time (mg / h), stomach_emptying: the rate of gastric emptying (mg / h). Maximum gastric emptying rate (mg / h) Half-maximal gastric emptying inhibition (mg), A_stomach: amount of nitrite in the stomach (mg), Δt: time step (h), stomach_dose: amount of nitrite actually entering the gastric cavity after each nitrite intake (mg). The kinetic equation for small intestinal absorption is as follows: si_inflow=stomach_emptying Among them, dA_ si / dt: Rate of change of nitrite in the small intestine over time (mg / h), si_inflow: Small intestinal inflow rate (mg / h), si_outflow: Small intestinal outflow rate (mg / h), k_abs: Small intestinal absorption rate constant (h). -1 ), A_ si : Nitrite levels in the small intestine (mg).

5. The method for constructing the human nitrite physiological toxicokinetics model according to claim 1, characterized in that, The metabolic process is the first-pass metabolism in the liver; the first-pass metabolism in the liver includes the amount of nitrite entering and leaving the liver through the portal vein, and the metabolic rate in the liver. The portal vein concentration: Where Q_liver: liver blood flow rate (L / h), C_portal: portal vein nitrite concentration (mg / L); The kinetic equations for the input and output of nitrite are as follows: liver_inflow=Q_liver×C_portal Wherein, liver_inflow: liver inflow rate (mg / h), liver_outflow: liver outflow rate (mg / h), V_liver: liver volume (L), A_liver: amount of nitrite in the liver (mg), P_liver: liver-plasma partition coefficient; The kinetic equation for the metabolic rate is: Wherein, dA_liver / dt: the rate of change of nitrite content in the liver over time (mg / h). metabolic_rate: metabolic rate (mg / h) Maximum metabolic rate (mg / h) Michaelis constant (mg / L), C_liver: nitrite concentration in the liver (mg / L), A_liver: nitrite content in the liver (mg).

6. The method for constructing the human nitrite physiological toxicokinetics model according to claim 1, characterized in that, The distribution process includes tissue distribution and blood distribution; The kinetic equation for the distribution of the tissue is as follows: Where dA_organ / dt: rate of change of nitrite in tissue over time (mg / h), Q_organ: tissue blood flow rate (L / h), V_organ: tissue volume (L), P_organ: tissue-plasma partition coefficient, A_organ: amount of nitrite in tissue (mg), C_blood: nitrite concentration in blood (mg / L), δ: δ=10 -6 , to prevent the zero threshold (L); The kinetic equation for the distribution in the blood is as follows: Wherein, dA_blood / dt: the rate of change of nitrite in blood over time (mg / h), and A_blood: the amount of nitrite in blood (mg).

7. The method for constructing the human nitrite physiological toxicokinetics model according to claim 1, characterized in that, The kinetic equation for renal excretion is as follows: kidney_inflow=Q_kidney×C_blood Wherein, kidney_inflow: renal inflow rate (mg / h), kidney_outflow: renal outflow rate (mg / h), dA_kidney / dt: rate of change of nitrite in the kidney over time (mg / h), renal_clearance: renal clearance rate (mg / h), Q_kidney: renal blood flow rate (L / h), V_kidney: kidney volume (L), P_kidney: kidney-plasma partition coefficient, CL_renal: renal clearance rate (L / h), and A_kidney: amount of nitrite in the kidney (mg); The kinetic equation for the nitrite oxidation metabolism is as follows: Where, metabolic_rate: metabolic rate (mg / h), Maximum metabolic rate (mg / h) Michaelis constant (mg / L), C_liver: nitrite concentration in liver (mg / L), V_liver: nitrite amount in liver (mg); The dynamic differential equation for renal clearance of nitrite is: Wherein, renal_clearance: renal clearance rate (mg / h), V_kidney: kidney volume (L), CL_renal: renal clearance rate (L / h), and A_kidney: amount of nitrite in the kidney (mg).

8. The method for constructing the human nitrite physiological toxicokinetics model according to claim 1, characterized in that, The initial conditions of the model are: nitrite content in each compartment is 0, and the daily nitrite intake is 0.79 mg; the time step is 0.01 h; and the simulation duration is 24 h.

9. A physiological toxicokinetic model of human nitrite obtained by the method described in any one of claims 1 to 8.

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