An apparatus for simulating an in-vivo atrioventricular model and a method for accurately predicting detoxification effect of fat emulsion

Abstract

The application relates to the field of simulation devices and application methods of pharmacokinetics, in particular to a device for simulating an in-vivo two-compartment model and a method for accurately predicting the detoxification effect of fat emulsion, and independently designs a two-pool four-pump device, which comprises two pools for simulating a two-compartment system and four pump devices serving as a driving system for transporting liquid. The device has the characteristics of uniform stirring and constant system temperature, and adopts a dynamic environment of liquid continuous flow to simulate the distribution and elimination of drugs in the body. Based on the phenomenon that liposoluble drug molecules can be captured by fat emulsion and the capturing degree is positively correlated with the lipophilicity of the drugs, fat emulsion with adjustable flow rate is injected on the basis of the two-pool four-pump device, the change of the drug concentration is detected by using a high-performance liquid chromatograph, the dose-effect relationship between the fat emulsion infusion speed and the capturing effect of drugs with various properties is established, and the accuracy of the dose-effect relationship in in-vivo prediction is verified through animal experiments.

Description

Technical Field

[0001] This invention relates to the field of devices and methods for simulating drug metabolism kinetics, and particularly to a device for simulating an in vivo compartmental model and a method for accurately predicting the detoxification effect of fat emulsions. Background Technology

[0002] Currently, organ damage and even death caused by drug poisoning has become a pressing clinical problem. A wide variety of drugs can cause poisoning, and clinical treatment typically relies on conventional life support methods, including extracorporeal techniques such as gastric lavage, hemodialysis, hemofiltration, and peritoneal dialysis to accelerate drug clearance. Developing corresponding antidotes for common clinical poisoning drugs is the optimal approach to drug poisoning, but this method is extremely labor-intensive and time-consuming without corresponding economic benefits, thus attracting few pharmaceutical companies. The most urgent and best solution is to develop a non-specific antidote that can alleviate the damage to vital organs caused by most drugs and improve patient prognosis.

[0003] Fat emulsions are a type of non-specific antidote that has emerged in recent years. Some hospitals are already using them in the treatment of cardiac arrest caused by local anesthetics and drug poisoning caused by multiple medications. Among the proposed mechanisms of action of fat emulsions, the "lipid sink" theory is widely accepted. The lipid sink effect refers to the formation of an expanded intravascular lipid-soluble chamber after a large intravenous injection of fat emulsion. Because soybean oil in the fat emulsion has a high affinity for lipid-soluble drugs, it can attract lipid-soluble drug molecules from the blood to the lipid sink, away from vital organs where drugs tend to accumulate. This reduces the amount of drug available to exert its toxic effects and lowers the concentration of free drug in the blood.

[0004] Pharmacokinetics typically uses compartmental models to simulate the human body. As long as the rates of drug acceptance or elimination are similar in certain parts of the body, they can be grouped into one compartment. The compartmental model is merely an abstract concept for pharmacokinetic analysis and does not necessarily represent a specific anatomical location. Assuming that after a drug enters the body, it instantly reaches dynamic equilibrium in tissues with rich blood supply (such as blood, liver, and kidneys), and then reaches dynamic equilibrium in tissues with less blood supply or slower blood flow (such as fat, skin, and bone), these tissues can be respectively called the central compartment and the peripheral compartment, i.e., a two-compartment model. A drug concentration-time curve conforming to a two-compartment model can be divided into two parts: the distribution phase and the elimination phase. After rapid intravenous administration, the drug quickly reaches distribution equilibrium in the central compartment. After equilibrium, the drug in the central compartment is distributed to the peripheral compartment, and the drug concentration in the central compartment decreases rapidly, while the drug concentration in the peripheral compartment tissues gradually increases. This process is called the distribution phase. As distribution continues, the distribution in the central and peripheral compartments gradually reaches a dynamic equilibrium, and the drug concentration in the peripheral compartment tissues reaches its maximum value. After that, the drug is mainly eliminated from the central compartment, and the drug concentrations in the central and peripheral compartments decrease in parallel. This process is called the elimination phase.

[0005] In vitro pharmacokinetic technology is one of the emerging drug research methods in recent decades. It utilizes in vitro devices to study the pharmacokinetic process and pharmacodynamics of drugs, providing a basis for the formulation of rational in vivo dosing regimens. This technology requires an in vitro device that can simulate the in vivo pharmacokinetic process of drugs, i.e., an in vitro pharmacokinetic device. In vitro pharmacokinetic studies are often related to the in vitro bactericidal curves of antibacterial drugs, but there is currently no device design scheme that links in vitro pharmacokinetic devices with fat emulsions to capture drugs.

[0006] However, the specific methods of using fat emulsions in clinical practice are currently lacking clear guidance and standardization. Due to concerns about the side effects of rapid bolus injection of fat emulsions, hospitals mostly adopt a conservative infusion method to maintain the detoxification effect. However, fat emulsions utilize the principle of capturing lipophilic drugs within their intrinsic oil phase, making highly lipophilic drugs more easily and rapidly captured, reaching their maximum capture capacity. From the perspective of capture capacity and volume, the detoxification methods of fat emulsion infusion should not be treated equally; that is, highly lipophilic drugs may not require the same high dose of fat emulsion as less lipophilic drugs. Therefore, in order to eliminate the drug concentration in the body chambers to a safe range during infusion, the flow rate of fat emulsion infusion should also vary depending on the different lipophilicities of the drugs.

[0007] Therefore, there is an urgent need to develop a device that simulates the in vivo compartment model and a method for accurately predicting the detoxification effect of fat emulsions, so as to ensure effective detoxification while controlling the amount of fat emulsion used within a safe range. Summary of the Invention

[0008] In view of this, the purpose of this invention is to propose a device for simulating an in vivo compartmental model and a method for accurately predicting the detoxification effect of fat emulsion. By establishing a two-pool, four-pump device that simulates a compartmental system to reflect the concentration elimination changes of drugs in vivo, a fat emulsion with adjustable flow rate is then injected to study the dynamic change process of drug concentration, thereby establishing a dose-response relationship between fat emulsion infusion rate and the capture effect of drugs with various properties. Finally, animal experiments are combined to verify the accuracy of the dose-response relationship in vivo.

[0009] To achieve the above objectives, the present invention provides an apparatus for simulating an in vivo compartmental model and a method for accurately predicting the detoxification effect of fat emulsions.

[0010] An apparatus for simulating a compartmental model in vivo, characterized in that it comprises a simulated central compartment container and a simulated peripheral compartment container, a first high-speed peristaltic pump, a second high-speed peristaltic pump, a first low-speed peristaltic pump, a second low-speed peristaltic pump, an injection pump for injecting fat emulsion, a silicone tube, a first thermostatic magnetic stirrer and a second thermostatic magnetic stirrer.

[0011] Furthermore, the central chamber simulation container and the peripheral chamber simulation container are spaces for dynamic changes in drug concentration and for the interaction between the drug and the fat emulsion. The central chamber simulation container is mainly a space for drug elimination, while the peripheral chamber simulation container is a space for the balanced distribution of the mixed liquid in the system. The injection pump is responsible for infusing the fat emulsion with an adjustable flow rate. The first high-speed peristaltic pump and the second high-speed peristaltic pump have the same flow rate but opposite directions and are used to connect the central chamber simulation container and the peripheral chamber simulation container. As a driving system, they transport the liquid in equal quantities, thereby creating specific changes in the drug concentration in the two chambers.

[0012] Furthermore, the first low-speed peristaltic pump and the second low-speed peristaltic pump are used to connect to the central chamber simulation container, and respectively pump the drug-containing solution from the central chamber simulation container to the outside of the system and pump physiological saline from the outside of the system into the central chamber simulation container at a constant speed, so as to compensate for the elimination of drug solution and system solution.

[0013] Furthermore, the central chamber simulation container, the peripheral chamber simulation container, the first high-speed peristaltic pump, the second high-speed peristaltic pump, the first low-speed peristaltic pump, the second low-speed peristaltic pump, and the injection pump are connected by silicone tubing. The first and second thermostatic magnetic stirrers act on the first and second magnetic particles in the central chamber simulation container and the peripheral chamber simulation container, respectively, so that the drug is evenly dispersed in the entire liquid system and the system temperature is constant.

[0014] Furthermore, the central chamber simulation container and the peripheral chamber simulation container are any one of beakers, conical flasks, round-bottom flasks, and graduated cylinders.

[0015] Furthermore, the flow rates of the first and second high-speed peristaltic pumps are 42-43 mL / min.-1 The flow rates of the first and second low-speed peristaltic pumps are 4.5-6 mL / min. -1 .

[0016] Furthermore, the temperature of both the first and second thermostatic magnetic stirrers is 37°C, and the rotation speed is 400-500 rpm·min. -1 .

[0017] A method for accurately predicting the detoxification effect of fat emulsions includes the following steps:

[0018] S1. Operating System: Inject the drug solution into the central chamber simulation container and inject physiological saline into the peripheral chamber simulation container. Start the first constant temperature magnetic stirrer, the second constant temperature magnetic stirrer, the first high-speed peristaltic pump, and the second high-speed peristaltic pump to distribute the drug solution in the central chamber simulation container and the peripheral chamber simulation container in a dynamic environment of continuous liquid flow. The drug concentration in the central chamber simulation container decreases rapidly, while the drug concentration in the tissue of the peripheral chamber simulation container gradually increases. When the drug concentration in the central chamber simulation container and the drug concentration in the peripheral chamber simulation container are balanced, start the first low-speed peristaltic pump and the second low-speed peristaltic pump to pump physiological saline into the central chamber simulation container and simultaneously discharge the drug-containing solution in the central chamber simulation container at the same speed. The drug begins to be eliminated from the central chamber simulation container. Due to the continuous operation of the two high-speed peristaltic pumps, the drug concentration in the peripheral chamber simulation container and the central chamber simulation container decreases in parallel.

[0019] Blank control group: Without the addition of fat emulsion, the two-pool four-pump device was run, and the drug solution in the central chamber simulated container was taken at continuous time points to analyze the concentration changes;

[0020] Fat emulsion group: Fat emulsion was infused into the central chamber simulated container at different infusion rates. The two-pool four-pump device was run, and the drug solution in the central chamber simulated container was sampled at continuous time points to analyze the concentration changes.

[0021] Saline group: Saline was infused into the central chamber simulation container at the same infusion rate for each fat emulsion group. The two-pool four-pump device was run, and the drug solution in the central chamber simulation container was taken at continuous time points to analyze the concentration changes.

[0022] S2. Analysis of pharmacokinetic parameters: The changes in drug concentration in the central chamber of the simulated container at continuous time points were detected by high performance liquid chromatography to obtain the drug concentration-time curves of the blank control / fat emulsion / physiological saline group. A two-compartment model was established to obtain the key pharmacokinetic parameter: the area under the drug-time curve (AUC).

[0023] S3. Define the efficiency ratio: The difference between the AUC of the saline group and the AUC of the fat emulsion group is ΔAUC1, which reflects the capture efficiency of the fat emulsion. The difference between the AUC of the blank control group and the AUC of the fat emulsion group is ΔAUC2, which reflects the combined effect of the capture efficiency and volumetric efficiency of the fat emulsion. Dividing ΔAUC1 by ΔAUC2 yields the efficiency ratio of the fat emulsion at that flow rate, i.e., the proportion of the fat emulsion's capture efficiency to the sum of its capture efficiency and volumetric efficiency.

[0024] S4. Establish a predictive model: Using fat emulsion infusion rate and drug LogP as independent variables and efficacy ratio as the dependent variable, establish a multiple nonlinear regression model① to explore the influence of the two variables on the efficacy ratio, thus obtaining the dose-response relationship between fat emulsion infusion rate and the capture effect of various drugs:

[0025]

[0026] Where logP represents the lipophilicity of the drug, and Rate represents the infusion rate of the fat emulsion (mL·min). -1 ), with parameters a = 0.520, b = 0.355, c = 0.104, the fitted R² value. 2 Not less than 0.947;

[0027] S5. Animal experiment verification: After establishing an animal drug overdose poisoning model, the blank control / fat emulsion / physiological saline group was treated with different flow rates. Blood was collected at continuous time points to obtain the corresponding plasma drug concentration-time curves. The AUC of the blank control group, fat emulsion group and physiological saline group was obtained. ΔAUC1, ΔAUC2 and the efficacy ratio in vivo at this flow rate were further obtained.

[0028] S6. Assess prediction accuracy: Based on the multivariate nonlinear regression model①, calculate the corresponding predicted efficacy ratio for each drug and each fat emulsion in vivo, compare the predicted efficacy ratio with the actual efficacy ratio in vivo, and assess the accuracy of the dose-response relationship prediction in vivo.

[0029] Based on the concept of a two-compartment model, its drug concentration-time curve can be divided into two parts: the distribution phase and the elimination phase. After rapid intravenous injection, the drug quickly reaches distribution equilibrium in the central compartment simulated container. After equilibrium, the drug in the central compartment simulated container is distributed to the peripheral compartment. The drug concentration in the central compartment simulated container decreases rapidly, while the tissue drug concentration in the peripheral compartment simulated container gradually increases. This process is called the distribution phase. As distribution proceeds, the drug distribution in the central and peripheral compartment simulated containers gradually reaches dynamic equilibrium. Dynamic equilibrium is considered to be reached when the difference in drug mass between the central and peripheral compartment simulated containers is less than 0.01. At this time, the tissue drug concentration in the peripheral compartment simulated container reaches its maximum value. After that, the drug is mainly eliminated from the central compartment simulated container, and the drug concentrations in the central and peripheral compartment simulated containers decrease in parallel. This process is called the elimination phase.

[0030] Based on the drug blood concentration-time curves that conform to the characteristics of a two-compartment model in vivo, it was set that at the end of the 5-minute distribution phase, the drug concentration in the central compartment simulated container decreased to 25% of the initial concentration. Subsequently, within 70 minutes of the elimination phase, the drug concentrations in both the central and peripheral compartment simulated containers decreased to 5% of the initial drug concentration in the central compartment simulated container.

[0031] The flow rates of both the first and second high-speed peristaltic pumps were set to 42.7 mL / min. -1 The reasons for the flow rate setting are as follows:

[0032]

[0033]

[0034]

[0035] Substituting the simultaneous equations into t = 5 min, we can solve for ω. 高速蠕动泵 = 42.7 mL·min -1

[0036] Furthermore, the two low-speed peristaltic pumps were set to a flow rate of 4.6 mL / min. -1 The reasons for the flow rate setting are as follows:

[0037]

[0038] Substituting t = 70 min, we can solve for ω. 低速蠕动泵 = 4.6 mL·min -1 .

[0039] The beneficial effects of this invention are:

[0040] This invention provides an apparatus for simulating an in vivo compartmental model and a method for accurately predicting the detoxification effect of fat emulsions. The apparatus successfully establishes a simulated in vivo compartmental model, characterized by uniform stirring and constant system temperature, and employs a dynamic environment of continuous liquid flow to simulate the distribution and elimination of drugs in vivo. It can be used for research on drug metabolism kinetics, pharmacodynamics, and pharmacokinetic-pharmacodynamic combination models. Based on the phenomenon that lipophilic drug molecules are captured by fat emulsions and enter the intrinsic oil phase, this invention combines in vitro pharmacokinetic technology with the process of drug capture by fat emulsions, establishing an intuitive, convenient, and reliable method for accurately predicting the detoxification effect of fat emulsions.

[0041] This invention provides a device for simulating an in vivo compartmental model and a method for accurately predicting the detoxification effect of fat emulsions. The invention establishes a dose-response relationship between the fat emulsion infusion rate and the capture effect of drugs with different properties by injecting an adjustable flow rate of fat emulsion into the device and detecting changes in drug concentration using high-performance liquid chromatography (HPLC). Animal experiments are used to verify the accuracy of this dose-response relationship in vivo. Compared with existing research applications, this invention provides a clear definition of the appropriate infusion rate of fat emulsions in the process of drug poisoning treatment, providing theoretical and experimental support for the use of fat emulsion detoxification therapy. It also has significant guiding significance for the clinical dosage and usage of fat emulsions as a universal antidote. Attached Figure Description

[0042] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only for this invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0043] Figure 1 This is a schematic diagram of the device structure of the present invention;

[0044] Figure 2 This is a flowchart of the prediction method of the present invention;

[0045] Figure 3 This is a graph showing the change in the capture efficiency ratio of the six drugs in vitro as a function of fat emulsion infusion rate.

[0046] Figure 4 This is a graph showing the change in the capture efficiency ratio of the four drugs in vivo as a function of fat emulsion infusion flow rate.

[0047] Figure 5 This is a diagram showing the comparison between the predicted values ​​and the measured values ​​of four drugs in vivo, calculated using a multivariate nonlinear regression model.

[0048] Figure 6A diagram showing the comparison between in vivo and in vitro predicted values ​​and measured values ​​to assess the overall accuracy of the model's predictions.

[0049] The diagram is marked as follows:

[0050] 1. System solution compensation; 2. System drug solution elimination; 3. Central chamber simulation container; 4. Peripheral chamber simulation container; 5. First low-speed peristaltic pump; 6. Second low-speed peristaltic pump; 7. First high-speed peristaltic pump; 8. Second high-speed peristaltic pump; 9. Injection pump; 10. First thermostatic magnetic stirrer; 11. Second thermostatic magnetic stirrer; 12. First magnetic stirrer; 13. Second magnetic stirrer. Detailed Implementation

[0051] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0052] It should be noted that, unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains. The terms "first," "second," and similar terms used in this invention do not indicate any order, quantity, or importance, but are merely used to distinguish different components. Terms such as "comprising" or "including" mean that the element or object preceding the word encompasses the elements or objects listed following the word and their equivalents, without excluding other elements or objects. Terms such as "connected" or "linked" are not limited to physical or mechanical connections, but can include electrical connections, whether direct or indirect. Terms such as "upper," "lower," "left," and "right" are used only to indicate relative positional relationships; when the absolute position of the described object changes, the relative positional relationship may also change accordingly.

[0053] Example 1:

[0054] A device for simulating a compartmental model in vivo, such as Figure 1 As shown, it includes a central chamber simulation container 3, a peripheral chamber simulation container 4, a first high-speed peristaltic pump 7, a second high-speed peristaltic pump 8, a first low-speed peristaltic pump 5, a second low-speed peristaltic pump 6, a syringe pump 9, a silicone tube, a first thermostatic magnetic stirrer 10, and a second thermostatic magnetic stirrer 11.

[0055] The central chamber simulated container 3 and the peripheral chamber simulated container 4 are spaces for dynamic changes in drug concentration and for the interaction between the drug and the fat emulsion. The central chamber simulated container 3 is primarily a space for drug elimination; the peripheral chamber simulated container 4 is a space for the balanced distribution of the mixed liquid within the system. The injection pump 9 is responsible for infusing the fat emulsion at an adjustable flow rate. The first high-speed peristaltic pump 7 and the second high-speed peristaltic pump 8 have equal flow rates and opposite directions, connecting the central chamber simulated container 3 and the peripheral chamber simulated container 4, acting as a drive system to transport equal volumes of liquid, thereby establishing the drug concentration within the central chamber simulated container 3 and the peripheral chamber simulated container 4. Specific changes; the first low-speed peristaltic pump 5 and the second low-speed peristaltic pump 6 are used to connect the central chamber simulation container 3, respectively pumping out the drug-containing liquid from the central chamber simulation container 3 to the outside of the system and pumping an equal amount of physiological saline from the outside of the system into the central chamber simulation container 3, to be responsible for the elimination of drug solution 2 and the compensation of system solution 1; the silicone tube serves as the connecting pipe for each container; the first thermostatic magnetic stirrer 10 and the second thermostatic magnetic stirrer 11 act on the first magnetic element 12 and the second magnetic element 13 in the central chamber simulation container 3 and the peripheral chamber simulation container 4, respectively, so that the drug is evenly dispersed in the entire liquid system and the system temperature is constant.

[0056] Example 2: A method for accurately predicting the detoxification effect of fat emulsions, comprising the following steps:

[0057] S1. Operating apparatus system: 50 mL of a 20 μg·mL⁻¹ solution was prepared. -1 The lidocaine solution was injected into a 100 mL beaker serving as the central chamber simulation container 3, and 150 mL of drug-free physiological saline was injected into a 200 mL beaker serving as the peripheral chamber simulation container 4. The first thermostatic magnetic stirrer 10, the second thermostatic magnetic stirrer 11, the first high-speed peristaltic pump 7, and the second high-speed peristaltic pump 8 were started. The flow rate of the first high-speed peristaltic pump 7 and the second high-speed peristaltic pump 8 was 42.7 mL / min. -1 The drug solution is distributed in the central chamber simulated container 3 and the peripheral chamber simulated container 4 under a dynamic environment of continuous liquid flow. The drug concentration in the central chamber simulated container 3 decreases rapidly, while the drug concentration in the peripheral chamber simulated container 4 gradually increases. After 5 minutes, the drug concentrations in the central chamber simulated container 3 and the peripheral chamber simulated container 4 reach equilibrium. At this point, the first low-speed peristaltic pump 5 and the second low-speed peristaltic pump 6 are started, with both pumps set to a flow rate of 4.6 mL / min. -1 At this time, physiological saline is pumped into the central chamber simulation container 3, and at the same time, the drug-containing solution in the central chamber simulation container 3 is discharged at the same speed, and the drug begins to be eliminated from the central chamber simulation container 3. As the two high-speed peristaltic pumps continue to operate, the drug concentration in the peripheral chamber and the central chamber simulation container 3 decreases in parallel.

[0058] S2. Blank control group experiment: Under the condition of no fat emulsion, the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively, and the concentration change was analyzed;

[0059] S3. Fat emulsion group experiment: 12.8 mL / min -1 11.2 mL·min -1 9.6 mL·min -1 8 mL·min -1 6.4 mL·min -1 4.8 mL·min -1 3.2 mL·min -1 and 1.6 mL·min -1 Fat emulsion was infused into the central chamber simulated container 3 at an infusion rate. The two-pool four-pump device was run, and the drug solution in the central chamber simulated container 3 was sampled at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min to analyze the concentration changes.

[0060] S4. Saline group experiment: Saline was infused into the central chamber simulated container 3 at the same infusion rate as the fat emulsion group experiment. The two-pool four-pump device was run, and 400 μL of the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively. After centrifugation to remove the fat emulsion, the lower aqueous phase that was not captured by the fat emulsion was taken and the concentration change was analyzed by high performance liquid chromatography.

[0061] S5. Analyze pharmacokinetic parameters: Obtain the drug concentration-time curves of the blank control group, fat emulsion group, and saline group. Use PK Solver software to establish a two-compartment model and obtain the key pharmacokinetic parameter: the area under the drug concentration-time curve (AUC).

[0062] S6. Define the power ratio: ΔAUC1 is the difference between the AUC of the saline group and the AUC of the fat emulsion group, and ΔAUC2 is the difference between the AUC of the blank control group and the AUC of the fat emulsion group. The ratio is obtained by dividing ΔAUC1 by ΔAUC2.

[0063] S7. Establish a predictive model: Using fat emulsion infusion rate and drug LogP as independent variables and efficacy ratio as the dependent variable, establish a multiple nonlinear regression model① to explore the influence of the two variables on the efficacy ratio, thus obtaining the dose-response relationship between fat emulsion infusion rate and the capture effect of various drugs:

[0064]

[0065] Where logP represents the lipophilicity of the drug, and Rate represents the infusion rate of the fat emulsion (mL·min). -1 ), with parameters a = 0.520, b = 0.355, c = 0.104, the fitted R² value. 2 =0.9878.

[0066] Example 3: A method for accurately predicting the detoxification effect of fat emulsions, comprising the following steps:

[0067] S1. Operating apparatus system: 50 mL of a 20 μg·mL⁻¹ solution was prepared. -1 Mirtazapine solution was injected into a 100 mL beaker serving as the central chamber simulation container 3, and 150 mL of drug-free physiological saline was injected into a 200 mL beaker serving as the peripheral chamber simulation container 4. The first thermostatic magnetic stirrer 10, the second thermostatic magnetic stirrer 11, the first high-speed peristaltic pump 7, and the second high-speed peristaltic pump 8 were activated. The flow rate of the first high-speed peristaltic pump 7 and the second high-speed peristaltic pump 8 was 42.7 mL / min. -1 The drug solution is distributed in the central chamber simulated container 3 and the peripheral chamber simulated container 4 under a dynamic environment of continuous liquid flow. The drug concentration in the central chamber simulated container 3 decreases rapidly, while the drug concentration in the peripheral chamber simulated container 4 gradually increases. After 5 minutes, the drug concentrations in the central chamber simulated container 3 and the peripheral chamber simulated container 4 reach equilibrium. At this point, the first low-speed peristaltic pump 5 and the second low-speed peristaltic pump 6 are started, with both pumps set to a flow rate of 4.6 mL / min. -1 At this time, physiological saline is pumped into the central chamber simulation container 3, and at the same time, the drug-containing solution in the central chamber simulation container 3 is discharged at the same speed, and the drug begins to be eliminated from the central chamber simulation container 3. As the two high-speed peristaltic pumps continue to operate, the drug concentration in the peripheral chamber and the central chamber simulation container 3 decreases in parallel.

[0068] S2. Blank control group experiment: Under the condition of no fat emulsion, the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively, and the concentration change was analyzed;

[0069] S3. Fat emulsion group experiment: 8.96 mL / min -1 7.84 mL·min -1 6.72 mL·min -1 5.6 mL·min -1 4.48 mL·min -1 3.36 mL·min -1 2.24 mL·min -1 and 1.12 mL·min -1 Fat emulsion was infused into the central chamber simulated container 3 at an infusion rate. The two-pool four-pump device was run, and the drug solution in the central chamber simulated container 3 was sampled at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min to analyze the concentration changes.

[0070] S4. Saline group experiment: Saline was infused into the central chamber simulated container 3 at the same infusion rate as the fat emulsion group experiment. The two-pool four-pump device was run, and 400 μL of the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively. After centrifugation to remove the fat emulsion, the lower aqueous phase that was not captured by the fat emulsion was taken and the concentration change was analyzed by high performance liquid chromatography.

[0071] S5. Analyze pharmacokinetic parameters: Obtain the drug concentration-time curves of the blank control group, fat emulsion group, and saline group. Use PK Solver software to establish a two-compartment model and obtain the key pharmacokinetic parameter: the area under the drug concentration-time curve (AUC).

[0072] S6. Define the power ratio: ΔAUC1 is the difference between the AUC of the saline group and the AUC of the fat emulsion group, and ΔAUC2 is the difference between the AUC of the blank control group and the AUC of the fat emulsion group. The ratio is obtained by dividing ΔAUC1 by ΔAUC2.

[0073] S7. Establish a predictive model: Using fat emulsion infusion rate and drug LogP as independent variables and efficacy ratio as the dependent variable, establish a multiple nonlinear regression model① to explore the influence of the two variables on the efficacy ratio, thus obtaining the dose-response relationship between fat emulsion infusion rate and the capture effect of various drugs:

[0074]

[0075] Where logP represents the lipophilicity of the drug, and Rate represents the infusion rate of the fat emulsion (mL·min). -1 ), with parameters a = 0.520, b = 0.355, c = 0.104, the fitted R² value. 2 =0.947.

[0076] Example 4: A method for accurately predicting the detoxification effect of fat emulsions, comprising the following steps:

[0077] S1. Operating apparatus system: 50 mL of a 20 μg·mL⁻¹ solution was prepared. -1 Bupivacaine solution was injected into a 100 mL beaker serving as the central chamber simulation container 3, and 150 mL of drug-free physiological saline was injected into a 200 mL beaker serving as the peripheral chamber simulation container 4. The first thermostatic magnetic stirrer 10, the second thermostatic magnetic stirrer 11, the first high-speed peristaltic pump 7, and the second high-speed peristaltic pump 8 were activated. The flow rate of the first high-speed peristaltic pump 7 and the second high-speed peristaltic pump 8 was 42.7 mL / min. -1 The drug solution is distributed in the central chamber simulated container 3 and the peripheral chamber simulated container 4 under a dynamic environment of continuous liquid flow. The drug concentration in the central chamber simulated container 3 decreases rapidly, while the drug concentration in the peripheral chamber simulated container 4 gradually increases. After 5 minutes, the drug concentrations in the central chamber simulated container 3 and the peripheral chamber simulated container 4 reach equilibrium. At this point, the first low-speed peristaltic pump 5 and the second low-speed peristaltic pump 6 are started, with both pumps set to a flow rate of 4.6 mL / min. -1 At this time, physiological saline is pumped into the central chamber simulation container 3, and at the same time, the drug-containing solution in the central chamber simulation container 3 is discharged at the same speed, and the drug begins to be eliminated from the central chamber simulation container 3. As the two high-speed peristaltic pumps continue to operate, the drug concentration in the peripheral chamber and the central chamber simulation container 3 decreases in parallel.

[0078] S2. Blank control group experiment: Under the condition of no fat emulsion, the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively, and the concentration change was analyzed;

[0079] S3. Fat emulsion group experiment: 3.84 mL / min -1 3.36 mL·min -1 2.88 mL·min -1 2.4 mL·min -1 1.92 mL·min -1 1.44 mL·min -1 0.96 mL·min-1 and 0.48 mL·min -1 Fat emulsion was infused into the central chamber simulated container 3 at an infusion rate. The two-pool four-pump device was run, and the drug solution in the central chamber simulated container 3 was sampled at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min to analyze the concentration changes.

[0080] S4. Saline group experiment: Saline was infused into the central chamber simulated container 3 at the same infusion rate as the fat emulsion group experiment. The two-pool four-pump device was run, and 400 μL of the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively. After centrifugation to remove the fat emulsion, the lower aqueous phase that was not captured by the fat emulsion was taken and the concentration change was analyzed by high performance liquid chromatography.

[0081] S5. Analyze pharmacokinetic parameters: Obtain the drug concentration-time curves of the blank control group, fat emulsion group, and saline group. Use PK Solver software to establish a two-compartment model and obtain the key pharmacokinetic parameter: the area under the drug concentration-time curve (AUC).

[0082] S6. Define the power ratio: ΔAUC1 is the difference between the AUC of the saline group and the AUC of the fat emulsion group, and ΔAUC2 is the difference between the AUC of the blank control group and the AUC of the fat emulsion group. The ratio is obtained by dividing ΔAUC1 by ΔAUC2.

[0083] S7. Establish a predictive model: Using fat emulsion infusion rate and drug LogP as independent variables and efficacy ratio as the dependent variable, establish a multiple nonlinear regression model① to explore the influence of the two variables on the efficacy ratio, thus obtaining the dose-response relationship between fat emulsion infusion rate and the capture effect of various drugs:

[0084]

[0085] Where logP represents the lipophilicity of the drug, and Rate represents the infusion rate of the fat emulsion (mL·min). -1 ), with parameters a = 0.520, b = 0.355, c = 0.104, the fitted R² value. 2 =0.9923.

[0086] Example 5: A method for accurately predicting the detoxification effect of fat emulsions, comprising the following steps:

[0087] S1. Operating apparatus system: 50 mL of a 20 μg·mL⁻¹ solution was prepared. -1 Flucainide solution was injected into a 100 mL beaker serving as the central chamber simulation vessel 3, and 150 mL of drug-free physiological saline was injected into a 200 mL beaker serving as the peripheral chamber simulation vessel 4. The first thermostatic magnetic stirrer 10, the second thermostatic magnetic stirrer 11, the first high-speed peristaltic pump 7, and the second high-speed peristaltic pump 8 were activated. The flow rate of the first high-speed peristaltic pump 7 and the second high-speed peristaltic pump 8 was 42.7 mL / min. -1 The drug solution is distributed in the central chamber simulated container 3 and the peripheral chamber simulated container 4 under a dynamic environment of continuous liquid flow. The drug concentration in the central chamber simulated container 3 decreases rapidly, while the drug concentration in the peripheral chamber simulated container 4 gradually increases. After 5 minutes, the drug concentrations in the central chamber simulated container 3 and the peripheral chamber simulated container 4 reach equilibrium. At this point, the first low-speed peristaltic pump 5 and the second low-speed peristaltic pump 6 are started, with both pumps set to a flow rate of 4.6 mL / min. -1 At this time, physiological saline is pumped into the central chamber simulation container 3, and at the same time, the drug-containing solution in the central chamber simulation container 3 is discharged at the same speed, and the drug begins to be eliminated from the central chamber simulation container 3. As the two high-speed peristaltic pumps continue to operate, the drug concentration in the peripheral chamber and the central chamber simulation container 3 decreases in parallel.

[0088] S2. Blank control group experiment: Under the condition of no fat emulsion, the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively, and the concentration change was analyzed;

[0089] S3. Fat emulsion group experiment: 3.2 mL / min -1 2.8 mL·min -1 2.4 mL·min -1 2 mL·min -1 1.6 mL·min -1 1.2 mL·min -1 0.8 mL·min -1 and 0.4 mL·min -1 Fat emulsion was infused into the central chamber simulated container 3 at an infusion rate. The two-pool four-pump device was run, and the drug solution in the central chamber simulated container 3 was sampled at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min to analyze the concentration changes.

[0090] S4. Saline group experiment: Saline was infused into the central chamber simulated container 3 at the same infusion rate as the fat emulsion group experiment. The two-pool four-pump device was run, and 400 μL of the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively. After centrifugation to remove the fat emulsion, the lower aqueous phase that was not captured by the fat emulsion was taken and the concentration change was analyzed by high performance liquid chromatography.

[0091] S5. Analyze pharmacokinetic parameters: Obtain the drug concentration-time curves of the blank control group, fat emulsion group, and saline group. Use PK Solver software to establish a two-compartment model and obtain the key pharmacokinetic parameter: the area under the drug concentration-time curve (AUC).

[0092] S6. Define the power ratio: ΔAUC1 is the difference between the AUC of the saline group and the AUC of the fat emulsion group, and ΔAUC2 is the difference between the AUC of the blank control group and the AUC of the fat emulsion group. The ratio is obtained by dividing ΔAUC1 by ΔAUC2.

[0093] S7. Establish a predictive model: Using fat emulsion infusion rate and drug LogP as independent variables and efficacy ratio as the dependent variable, establish a multiple nonlinear regression model① to explore the influence of the two variables on the efficacy ratio, thus obtaining the dose-response relationship between fat emulsion infusion rate and the capture effect of various drugs:

[0094]

[0095] Where logP represents the lipophilicity of the drug, and Rate represents the infusion rate of the fat emulsion (mL·min). -1 ), with parameters a = 0.520, b = 0.355, c = 0.104, the fitted R² value. 2 =0.947.

[0096] Example 6: A method for accurately predicting the detoxification effect of fat emulsions, comprising the following steps:

[0097] S1. Operating apparatus system: 50 mL of a 20 μg·mL⁻¹ solution was prepared. -1 Amitriptyline solution was injected into a 100 mL beaker serving as the central chamber simulation container 3, and 150 mL of drug-free physiological saline was injected into a 200 mL beaker serving as the peripheral chamber simulation container 4. The first thermostatic magnetic stirrer 10, the second thermostatic magnetic stirrer 11, the first high-speed peristaltic pump 7, and the second high-speed peristaltic pump 8 were activated, with a flow rate of 42.7 mL / min.-1 The drug solution is distributed in the central chamber simulated container 3 and the peripheral chamber simulated container 4 under a dynamic environment of continuous liquid flow. The drug concentration in the central chamber simulated container 3 decreases rapidly, while the drug concentration in the peripheral chamber simulated container 4 gradually increases. After 5 minutes, the drug concentrations in the central chamber simulated container 3 and the peripheral chamber simulated container 4 reach equilibrium. At this point, the first low-speed peristaltic pump 5 and the second low-speed peristaltic pump 6 are started, with both pumps set to a flow rate of 4.6 mL / min. -1 At this time, physiological saline is pumped into the central chamber simulation container 3, and at the same time, the drug-containing solution in the central chamber simulation container 3 is discharged at the same speed, and the drug begins to be eliminated from the central chamber simulation container 3. As the two high-speed peristaltic pumps continue to operate, the drug concentration in the peripheral chamber and the central chamber simulation container 3 decreases in parallel.

[0098] S2. Blank control group experiment: Under the condition of no fat emulsion, the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively, and the concentration change was analyzed;

[0099] S3. Fat emulsion group experiment: 1.28 mL / min -1 1.12 mL·min -1 0.96 mL·min -1 0.8 mL·min -1 0.64 mL·min -1 0.48 mL·min -1 0.32 mL·min -1 and 0.16 mL·min -1 Fat emulsion was infused into the central chamber simulated container 3 at an infusion rate. The two-pool four-pump device was run, and the drug solution in the central chamber simulated container 3 was sampled at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min to analyze the concentration changes.

[0100] S4. Saline group experiment: Saline was infused into the central chamber simulated container 3 at the same infusion rate as the fat emulsion group experiment. The two-pool four-pump device was run, and 400 μL of the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively. After centrifugation to remove the fat emulsion, the lower aqueous phase that was not captured by the fat emulsion was taken and the concentration change was analyzed by high performance liquid chromatography.

[0101] S5. Analyze pharmacokinetic parameters: Obtain the drug concentration-time curves of the blank control group, fat emulsion group, and saline group. Use PK Solver software to establish a two-compartment model and obtain the key pharmacokinetic parameter: the area under the drug concentration-time curve (AUC).

[0102] S6. Define the power ratio: ΔAUC1 is the difference between the AUC of the saline group and the AUC of the fat emulsion group, and ΔAUC2 is the difference between the AUC of the blank control group and the AUC of the fat emulsion group. The ratio is obtained by dividing ΔAUC1 by ΔAUC2.

[0103] S7. Establish a predictive model: Using fat emulsion infusion rate and drug LogP as independent variables and efficacy ratio as the dependent variable, establish a multiple nonlinear regression model① to explore the influence of the two variables on the efficacy ratio, thus obtaining the dose-response relationship between fat emulsion infusion rate and the capture effect of various drugs:

[0104]

[0105] Where logP represents the lipophilicity of the drug, and Rate represents the infusion rate of the fat emulsion (mL·min). -1 ), with parameters a = 0.520, b = 0.355, c = 0.104, the fitted R² value. 2 =0.9972.

[0106] Example 7: A method for accurately predicting the detoxification effect of fat emulsions, comprising the following steps:

[0107] S1. Operating apparatus system: 50 mL of a 20 μg·mL⁻¹ solution was prepared. -1 Sertraline solution was injected into a 100 mL beaker serving as the central chamber simulation container 3, and 150 mL of drug-free physiological saline was injected into a 200 mL beaker serving as the peripheral chamber simulation container 4. The first thermostatic magnetic stirrer 10, the second thermostatic magnetic stirrer 11, the first high-speed peristaltic pump 7, and the second high-speed peristaltic pump 8 were activated. The flow rate of the first high-speed peristaltic pump 7 and the second high-speed peristaltic pump 8 was 42.7 mL / min. -1The drug solution is distributed in the central chamber simulated container 3 and the peripheral chamber simulated container 4 under a dynamic environment of continuous liquid flow. The drug concentration in the central chamber simulated container 3 decreases rapidly, while the drug concentration in the peripheral chamber simulated container 4 gradually increases. After 5 minutes, the drug concentrations in the central chamber simulated container 3 and the peripheral chamber simulated container 4 reach equilibrium. At this point, the first low-speed peristaltic pump 5 and the second low-speed peristaltic pump 6 are started, with both pumps set to a flow rate of 4.6 mL / min. -1 At this time, physiological saline is pumped into the central chamber simulation container 3, and at the same time, the drug-containing solution in the central chamber simulation container 3 is discharged at the same speed, and the drug begins to be eliminated from the central chamber simulation container 3. As the two high-speed peristaltic pumps continue to operate, the drug concentration in the peripheral chamber and the central chamber simulation container 3 decreases in parallel.

[0108] S2. Blank control group experiment: Under the condition of no fat emulsion, the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively, and the concentration change was analyzed;

[0109] S3. Fat emulsion group experiment: 0.64 mL / min -1 0.56 mL·min -1 0.48 mL·min -1 0.4 mL·min -1 0.32 mL·min -1 0.24 mL·min -1 0.16 mL·min -1 and 0.08 mL·min -1 Fat emulsion was infused into the central chamber simulated container 3 at an infusion rate. The two-pool four-pump device was run, and the drug solution in the central chamber simulated container 3 was sampled at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min to analyze the concentration changes.

[0110] S4. Saline group experiment: Saline was infused into the central chamber simulated container 3 at the same infusion rate as the fat emulsion group experiment. The two-pool four-pump device was run, and 400 μL of the drug solution in the central chamber simulated container 3 was taken at 1 min, 2 min, 3 min, 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min and 60 min respectively. After centrifugation to remove the fat emulsion, the lower aqueous phase that was not captured by the fat emulsion was taken and the concentration change was analyzed by high performance liquid chromatography.

[0111] S5. Analyze pharmacokinetic parameters: Obtain the drug concentration-time curves of the blank control group, fat emulsion group, and saline group. Use PK Solver software to establish a two-compartment model and obtain the key pharmacokinetic parameter: the area under the drug concentration-time curve (AUC).

[0112] S6. Define the power ratio: ΔAUC1 is the difference between the AUC of the saline group and the AUC of the fat emulsion group, and ΔAUC2 is the difference between the AUC of the blank control group and the AUC of the fat emulsion group. The ratio is obtained by dividing ΔAUC1 by ΔAUC2.

[0113] S7. Establish a predictive model: Using fat emulsion infusion rate and drug LogP as independent variables and efficacy ratio as the dependent variable, establish a multiple nonlinear regression model① to explore the influence of the two variables on the efficacy ratio, thus obtaining the dose-response relationship between fat emulsion infusion rate and the capture effect of various drugs:

[0114]

[0115] Where logP represents the lipophilicity of the drug, and Rate represents the infusion rate of the fat emulsion (mL·min). -1 ), with parameters a = 0.520, b = 0.355, c = 0.104, the fitted R² value. 2 =0.9991.

[0116] Example 8: Animal experiment verification:

[0117] S1. Ten-week-old male New Zealand white rabbits were selected and divided into an experimental group and a control group, with six rabbits in each group. Both groups were administered medication via the marginal ear vein at a dose of 0.16 mL / min. -1 ·kg -1 Lidocaine was injected at a flow rate of [unspecified], followed immediately by an infusion of 10 mL / kg into the experimental group. -1 A 30% fat emulsion was administered to the control group at a dose of 10 mL / kg. -1Blood samples of approximately 1 mL were collected via the central auricular artery at 0 min, 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min after the start of the infusion of physiological saline. The collected blood samples were centrifuged at 3200 g for 5 min at room temperature, and the supernatant was centrifuged at 22000 g for 15 min. 75 μL of plasma was collected, and 150 μL of acetonitrile was added to the plasma. The mixture was vortexed and centrifuged at 14000 g for 5 min. The supernatant was used to analyze the drug concentration using a high-performance liquid chromatography (HPLC) instrument, and the pharmacokinetic parameters were calculated using a two-compartment model in PK Solver software.

[0118] S2. Based on the multivariate nonlinear regression model①, the corresponding predicted efficacy ratio is calculated for the infusion rate of each drug fat emulsion in New Zealand white rabbits. The predicted efficacy ratio is compared with the corresponding efficacy ratio in actual New Zealand white rabbits to evaluate the accuracy of the dose-response relationship prediction in New Zealand white rabbits.

[0119] Example 9: Animal Experiment Verification:

[0120] S1. Ten-week-old male New Zealand white rabbits were selected and divided into an experimental group and a control group, with six rabbits in each group. Both groups were administered medication via the marginal ear vein at a dose of 0.32 mL / min. -1 ·kg -1 Bupivacaine was injected at a flow rate of [unspecified], followed immediately by an infusion of 10 mL / kg [unspecified] into the experimental group. -1 A 30% fat emulsion was administered to the control group at a dose of 10 mL / kg. -1 Blood samples of approximately 1 mL were collected via the central auricular artery at 0 min, 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min after the start of the infusion of physiological saline. The collected blood samples were centrifuged at 3200 g for 5 min at room temperature, and the supernatant was centrifuged at 22000 g for 15 min. 75 μL of plasma was collected, and 150 μL of acetonitrile was added to the plasma. The mixture was vortexed and centrifuged at 14000 g for 5 min. The supernatant was used to analyze the drug concentration using a high-performance liquid chromatography (HPLC) instrument, and the pharmacokinetic parameters were calculated using a two-compartment model in PK Solver software.

[0121] S2. Based on the multivariate nonlinear regression model①, the corresponding predicted efficacy ratio is calculated for the infusion rate of each drug fat emulsion in New Zealand white rabbits. The predicted efficacy ratio is compared with the corresponding efficacy ratio in actual New Zealand white rabbits to evaluate the accuracy of the dose-response relationship prediction in New Zealand white rabbits.

[0122] Example 10: Animal experiment verification:

[0123] S1. Ten-week-old male New Zealand white rabbits were selected and divided into an experimental group and a control group, with six rabbits in each group. Both groups were treated with intravenous infusion via the marginal ear vein at a dose of 0.48 mL / min. -1 ·kg -1 Amitriptyline was injected at a flow rate of 10 mL / kg, followed immediately by an infusion of 10 mL / kg into the experimental group. -1 A 30% fat emulsion was administered to the control group at a dose of 10 mL / kg. -1 Blood samples of approximately 1 mL were collected via the central auricular artery at 0 min, 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min after the start of the infusion of physiological saline. The collected blood samples were centrifuged at 3200 g for 5 min at room temperature, and the supernatant was centrifuged at 22000 g for 15 min. 75 μL of plasma was collected, and 150 μL of acetonitrile was added to the plasma. The mixture was vortexed and centrifuged at 14000 g for 5 min. The supernatant was used to analyze the drug concentration using a high-performance liquid chromatography (HPLC) instrument, and the pharmacokinetic parameters were calculated using a two-compartment model in PK Solver software.

[0124] S2. Based on the multivariate nonlinear regression model①, the corresponding predicted efficacy ratio is calculated for the infusion rate of each drug fat emulsion in New Zealand white rabbits. The predicted efficacy ratio is compared with the corresponding efficacy ratio in actual New Zealand white rabbits to evaluate the accuracy of the dose-response relationship prediction in New Zealand white rabbits.

[0125] Example 11: Animal experiment verification:

[0126] S1. Ten-week-old male New Zealand white rabbits were selected and divided into an experimental group and a control group, with six rabbits in each group. Both groups were administered medication via the marginal ear vein at a dose of 0.64 mL / min. -1 ·kg -1 Sertraline was injected at a flow rate of [missing information], followed immediately by an infusion of 10 mL / kg [missing information] into the experimental group. -1 A 30% fat emulsion was administered to the control group at a dose of 10 mL / kg. -1 Blood samples of approximately 1 mL were collected via the central auricular artery at 0 min, 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min after the start of the infusion of physiological saline. The collected blood samples were centrifuged at 3200 g for 5 min at room temperature, and the supernatant was centrifuged at 22000 g for 15 min. 75 μL of plasma was collected, and 150 μL of acetonitrile was added to the plasma. The mixture was vortexed and centrifuged at 14000 g for 5 min. The supernatant was used to analyze the drug concentration using a high-performance liquid chromatography (HPLC) instrument, and the pharmacokinetic parameters were calculated using a two-compartment model in PK Solver software.

[0127] S2. Based on the multivariate nonlinear regression model①, the corresponding predicted efficacy ratio is calculated for the infusion rate of each drug fat emulsion in New Zealand white rabbits. The predicted efficacy ratio is compared with the corresponding efficacy ratio in actual New Zealand white rabbits to evaluate the accuracy of the dose-response relationship prediction in New Zealand white rabbits.

[0128] The results are shown in Tables 1 and 2:

[0129] Table 1 Drug Information

[0130] drug LogP Indications Lidocaine 2.44 Local anesthesia mirtazapine 2.90 Various types of depression Bupicaine 3.41 Local anesthesia Flucarbide 3.78 Supraventricular tachycardia, atrial fibrillation, etc. Amitriptyline 4.92 Anxiety-type and agitation-type depression Sertraline 5.51 Obsessive-compulsive disorder, various types of depression

[0131] Table 2 Gradient of fat emulsion infusion rates for different drugs

[0132] drug LogP <![CDATA[Infusion rate gradient of fat emulsion (mL·min -1 )]]> Lidocaine 2.44 12.8、11.2、9.6、8、6.4、4.8、3.2、1.6 mirtazapine 2.90 8.96、7.84、6.72、5.6、4.48、3.36、2.24、1.12 Bupicaine 3.41 3.84、3.36、2.88、2.4、1.92、1.44、0.96、0.48 Flucarbide 3.78 3.2、2.8、2.4、2、1.6、1.2、0.8、0.4 Amitriptyline 4.92 1.28、1.12、0.96、0.8、0.64、0.48、0.32、0.16 Sertraline 5.51 0.64、0.56、0.48、0.4、0.32、0.24、0.16、0.08

[0133] Table 3. Prediction accuracy results of animal experiment evaluation in Examples 8-11

[0134] drug <![CDATA[R 2 ]]> Lidocaine 0.9878 Bupicaine 0.9923 Amitriptyline 0.9972 Sertraline 0.9991

[0135] Data Analysis:

[0136] As shown in Tables 1, 2, and 3, the model predictions and experimental results are in precise agreement (R²). 2 =0.9955). Based on the in vitro and in vivo prediction results of each drug, it can be seen that the higher the lipophilicity of the drug, the closer the predicted value of the multiple nonlinear regression model is to the measured value in vivo.

[0137] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention (including the claims) is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in the details for the sake of brevity.

[0138] This invention is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A method for accurately predicting the detoxification effect of fat emulsions, characterized in that, Includes the following steps: S1. Operating system: The drug solution is injected into the central chamber simulation container (3), and the physiological saline is injected into the peripheral chamber simulation container (4). The first thermostatic magnetic stirrer (10), the second thermostatic magnetic stirrer (11), the first high-speed peristaltic pump (7), and the second high-speed peristaltic pump (8) are started to distribute the drug solution in the central chamber simulation container (3) and the peripheral chamber simulation container (4) in a dynamic environment of continuous liquid flow. When the drug concentration in the central chamber simulation container (3) and the peripheral chamber simulation container (4) is balanced, the first low-speed peristaltic pump (5) and the second low-speed peristaltic pump (6) are started to pump the physiological saline into the central chamber simulation container (3) through the first low-speed peristaltic pump (5) and to discharge the drug-containing solution in the central chamber simulation container (3) through the second low-speed peristaltic pump (6). Blank control group: Under the condition of no fat emulsion, the device was run and the drug solution in the simulated container (3) in the central chamber was taken at continuous time points. The change of drug concentration was detected by high performance liquid chromatography and the drug concentration-time curve was obtained. Fat emulsion group: Fat emulsion was injected into the central chamber simulation container (3) at different infusion rates by the injection pump (9). The device was run and the drug solution in the central chamber simulation container (3) was taken at continuous time points. The change of drug concentration was detected by high performance liquid chromatography and the drug concentration-time curve was obtained. Saline group: Saline was infused into the central chamber simulation container (3) at the same infusion rate as each fat emulsion using an injection pump (9). The device was run, and the drug solution in the central chamber simulation container (3) was taken at continuous time points. The change in drug concentration was detected by high performance liquid chromatography to obtain the drug concentration-time curve. S2. Analysis of pharmacokinetic parameters: A two-compartment model was established to obtain the area under the drug concentration-time curves (AUC) for the blank control group, fat emulsion group, and saline group; S3. Define the efficiency ratio: ΔAUC1 is obtained by calculating the difference between the AUC of the saline group and the AUC of the fat emulsion group, and ΔAUC2 is obtained by calculating the difference between the AUC of the blank control group and the AUC of the fat emulsion group. ΔAUC1 is divided by ΔAUC2 to obtain the efficiency ratio of the fat emulsion at this infusion rate. S4. Establish a predictive model: Establish a multivariate nonlinear regression model: ΔAUC1 / ΔAUC2 = (logP) a × (bRate c ) Where logP represents the lipophilicity of the drug, Rate represents the infusion rate of the fat emulsion, parameters a=0.520, b=0.355, c=0.104, and the fitted R0 is... 2 The dose-response relationship between the fat emulsion infusion rate and the capture effect of drugs with different properties was obtained with a value not less than 0.

947. The central chamber simulation container (3) and the peripheral chamber simulation container (4) are connected by a silicone tube by a first high-speed peristaltic pump (7) and a second high-speed peristaltic pump (8). The first high-speed peristaltic pump (7) and the second high-speed peristaltic pump (8) have the same flow rate and opposite direction, and the flow rate is 42-43 mL·min. -1 This is used to transport liquid in equal quantities between a central chamber simulation container (3) and a peripheral chamber simulation container (4) to simulate the distribution phase; a first low-speed peristaltic pump (5), a second low-speed peristaltic pump (6), and a syringe pump (9) are provided on one side of the central chamber simulation container (3). The first low-speed peristaltic pump (5) and the second low-speed peristaltic pump (6) have the same flow rate but opposite directions, and the flow rate is 4.5-6 mL·min. -1 The first low-speed peristaltic pump (5) is used to pump physiological saline from outside the system into the central chamber simulation container (3) at a constant speed to compensate for the system solution. The second low-speed peristaltic pump (6) is used to pump the drug-containing solution in the central chamber simulation container (3) out of the system at a constant speed to achieve drug elimination. The syringe pump (9) is used to infuse fat emulsion into the central chamber simulation container (3) at an adjustable flow rate. The bottom of the central chamber simulation container (3) and the peripheral chamber simulation container (4) are respectively equipped with a first thermostatic magnetic stirrer (10) and a second thermostatic magnetic stirrer (11). The temperature of the first thermostatic magnetic stirrer (10) and the second thermostatic magnetic stirrer (11) are both 37°C and the rotation speed is 400-500 rpm·min. -1 The central chamber simulation container (3) and the peripheral chamber simulation container (4) are respectively provided with a first magnet (12) and a second magnet (13).

2. The method according to claim 1, characterized in that, The central chamber simulation container (3) and the peripheral chamber simulation container (4) are any one of beakers, conical flasks, round-bottom flasks and graduated cylinders.

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