WO2006057268A1 - Simulation apparatus and program - Google Patents

Abstract

[PROBLEMS] Conventional simulation apparatuses for drug absorption, etc. have been unable to simulate, for example, drug absorption or excretion taking into consideration any individual specificity and living organism (cell) stimulation and pathological change between before and after drug administration. [MEANS FOR SOLVING PROBLEMS] There is provided a simulation apparatus for simulating of drug absorption or/and excretion on the basis of drug information being information relating to a drug as simulation object and bioinformation relating to information on living organism, which simulation apparatus is adapted to accept bioinformation dynamically even during performing of the simulation. This biosimulation apparatus is able to simulate, for example, drug absorption or excretion taking into consideration any individual specificity and living organism (cell) stimulation and pathological change between before and after drug administration.

Description

 Specification

 Simulation apparatus and program

 Technical field

 [oooi] The present invention relates to a simulation apparatus for simulating drug absorption or Z and excretion, a program thereof, and the like.

 Background art

 There are the following simulation devices as conventional simulation devices for drug absorption and the like. In other words, this simulation device calculates the time course of drug behavior (blood concentration) in the body as well as the drug-specific characteristics (solubility, fat solubility, membrane permeability, metabolic stability, etc.). In addition, this simulation apparatus was designed to evaluate the drug absorption at the normal normal time only based on the properties of the drug.

 [0003] On the other hand, there is a cell simulation apparatus that simulates the operation and function of cells (see Non-Patent Document 1). The cell simulation device, which calculates the transport of ions and water in the cell and the electric potential of the membrane surface, mainly focuses on analyzing and elucidating the intracellular activity.

 In addition, a technique for a simulation apparatus for epithelial cells inside an epithelial cell model is also disclosed (see Non-Patent Document 2, Non-Patent Document 3, and Non-Patent Document 4).

 Furthermore, it has been elucidated that when human SGLT1 transports 1 mole of glucose, 2 moles of Na + ions and 264 moles of H 2 O molecule are transported simultaneously (see Non-Patent Document 5).

 2

 Non-Patent Document 1: M. Tomita, K. Hashimoto, K. Takahashi, T. Shimizu, Y. Matsuzaki, F. Miyoshi, K. Saito, S. Tanida, K. Yugi, JC Ven ter, and CA Hutchison III, 「E- CEI: software environment for whole― cell simulationj in Bioinformatics, vol. 15, no. 1, pp. 72 -84, 1999

 Non-Patent Document 2: A. M. Weinstein et al., 1990, J. Gen. Physiol., 96, 319-344.

Non-Patent Document 3: AM Weinstein, Am. J. Physiol., 1992, 263, F 748- 798,

 Non-patent literature 4: Parent et al., J Membr. Biol. 125: 63- 79, 1992 Non-patent literature 5: Donald DF Loo, Ernest M. Wright and Thomas Zeuthen, Water pumps, Journal of Physiology (2002), 542 (pt. 1), pp. 53-60

 Disclosure of the invention

 Problems to be solved by the invention

[0004] However, the conventional simulation device for drug absorption, etc. is a simulation for drug absorption or excretion taking into account individual differences, biological (cell) stimulation before and after drug administration, and pathological changes. could not.

 Means for solving the problem

 [0005] The simulation apparatus according to the first aspect of the present invention is based on drug information, which is information about a drug to be simulated, and biological information about biological information.

This is a simulation apparatus that simulates Z, excretion, and the like, and that dynamically receives the biological information even during the simulation.

 A powerful simulation device can simulate drug absorption or Z and excretion taking into account individual differences, biological (cell) stimulation before and after drug administration, or pathological changes.

 [0006] The simulation device of the second invention is a simulation in which the pharmacokinetic information in the simulation device of the first invention includes at least part information indicating a part that absorbs the drug and state information indicating the state of the drug. Device.

 The powerful simulation device can simulate for each part of a living body, drug absorption or Z and excretion taking into account individual differences, stimulation of a living body (cell) before and after drug administration, or pathological changes.

[0007] Further, in the simulation apparatus according to the third aspect of the invention, in the first and second simulation apparatuses, the biological information receiving unit is an output of a cell simulation apparatus capable of simulating intracellular movement. It is a simulation device that accepts certain biological information. In addition, fine The vesicle is preferably an epithelial cell. Further, the simulation apparatus may accept biological information from the cell simulation apparatus indirectly.

 The powerful simulation device can accurately simulate drug absorption or Z and excretion taking into account individual differences, biological (cell) stimulation before and after drug administration, or pathological changes.

 The invention's effect

 [0008] The present invention can simulate drug absorption or Z and excretion in consideration of individual differences, body (cell) stimulation before and after drug administration, or pathological changes. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, embodiments of an information processing system including a simulation apparatus will be described with reference to the drawings. In addition, since the component which attached | subjected the same code | symbol in embodiment performs the same operation | movement, repeated description may be abbreviate | omitted.

 FIG. 1 is a block diagram of the information processing system in the present embodiment. The information processing system includes a simulation device 11, a cell simulation device 12, and a control device 13. The simulation device 11 simulates drug absorption or Z and excretion. Here, the cell simulation device 12 performs simulation of biological functions (functions of organs, cells, tissues, etc.), but in this embodiment, the simulation device 11 mainly uses simulations of cell functions and operations. Therefore, the cell simulation device 12 will be referred to. The cell is mainly an epithelial cell. The control device 1 3 performs control for the functioning of the entire information processing system, such as passing information between the simulation device 11 and the cell simulation device 12, and giving a trigger for the operation of the simulation device 11 and the cell simulation device 12. Do.

 The simulation apparatus 11 includes an instruction receiving unit 1101, a drug information receiving unit 1102, a biological information acquisition instruction unit 1103, a biological information receiving unit 1104, an arithmetic expression storage unit 1105, an arithmetic execution unit 1106, and an output unit 1107.

[0011] The cell simulation device 12 includes a second instruction receiving unit 1201, a functional element information storage unit 1202, a static structure management unit 1203, a parameter management unit 1204, a simulation command receiving unit 1 205, a functional element identifier acquisition unit 1206, Parameter acquisition unit 1207, execution unit 1208, living body An information transmission unit 1209 is provided. The static structure management unit 1203 includes cell function management means 12031 and organ cell management means 12032. However, the static structure management unit 1203 includes the cell function management unit 12031 and the organ cell management unit 12032 is an example of the internal structure of the static structure management unit 1203.

 The control device 13 includes an instruction unit 1301, a biological information acquisition instruction receiving unit 1302, a biological information acquisition unit 1303, a biological information adding unit 1304, an execution result acquisition unit 1305, and an execution result display unit 1306.

 [0012] The instruction receiving unit 1101 receives a start instruction which is an instruction to start a drug absorption simulation. The acceptance is usually reception from the control device 13, but may be acceptance of a start instruction by manual input by the user. The instruction receiving unit 1101 can be realized by a wireless or wired communication unit, a device driver for an input unit such as a numeric keypad or a keyboard, a control software for a menu screen, and the like.

 [0013] Drug information receiving section 1102 receives drug information that is information related to a drug to be simulated. The drug information includes, for example, information for identifying a drug, drug solubility, dissolution rate constant, membrane permeability coefficient, and the like. Drug information receiving section 1102 may receive only information for identifying a drug, or may accept drug solubility, dissolution rate constant, membrane permeability coefficient, and the like. The drug information input means may be anything such as a numeric keypad, keyboard, mouse or menu screen. The drug information receiving unit 1102 may perform processing for reading out drug information held in advance. In such a case, reading corresponds to acceptance. The drug information receiving unit 1102 can be realized by a device driver for input means such as a numeric keypad or a keyboard, control software for a menu screen, or the like. Further, the reception in the drug information reception unit 1102 may be reception by the control device 13 as much as possible.

The biological information acquisition instruction unit 1103 transmits a biological information acquisition instruction for instructing acquisition of biological information to the control device 13. Biological information is information related to biological information, for example, information indicating the movement of cell ions (for example, Na ions, Ka ions, etc.), information indicating the movement of water, membrane potential, pH, cell volume. And so on. The information indicating the movement of water is, for example, the water absorption rate. The biometric information acquisition instruction is, for example, transmission of a message for acquiring biometric information. The structure of the biometric information acquisition instruction does not matter. Biometric information collection The acquisition instruction unit 1103 can be realized by, for example, a wireless or wired communication unit.

The biometric information receiving unit 1104 receives biometric information related to biometric information. The biological information receiving unit 1104 normally receives biological information related to biological information before the start of the drug absorption simulation and during the drug absorption simulation. However, the biometric information receiving unit 1104 may receive the biometric information once before the start of the drug absorption simulation, or may receive the biometric information only once during the drug absorption simulation. . The reception of biometric information before the start of drug absorption simulation may be performed by reading out the recording medium force or reading out biometric information by a program when the biometric information is embedded in the program. That is, the biometric information receiving method in the biometric information receiving unit 1104 may change. If the biometric information is not received before the start of the drug absorption simulation, the simulation device 11 may store the drug absorption simulation based on the initial biometric information held in advance, for example! Will be done. When biometric information is received before the start of drug absorption simulation, drug absorption simulation can be performed in consideration of individual differences in simulation targets and differences in individual states. When biological information is received during drug absorption simulation, drug absorption simulation according to dynamic biological information changes is possible. The reception of biological information in the biological information reception unit 1104 is reception of biological information from the control device 13, for example. In addition, the reception of biological information in the biological information reception unit 1104 may be, for example, reading of biological information having a power of a recording medium, manual input of biological information by a user, or a control device. It may be the reception of biometric information from an external device other than 13. The biometric information receiving unit 1104 can be realized by, for example, a wireless or wired communication means.

[0016] The arithmetic expression storage unit 1105 stores a pharmacokinetic information output arithmetic expression that is an arithmetic expression for outputting pharmacokinetic information that is information related to absorption or excretion of the drug, using the drug information and biological information as parameters. Yes. The pharmacokinetic information includes, for example, at least site information indicating a site where the drug is absorbed or excreted and state information indicating the state of the drug. Pharmacokinetic information includes, for example, drug absorption rate, drug metabolism rate, drug urinary excretion rate, first-pass metabolic rate, drug blood concentration, drug absorption, drug renal excretion, drug Including the amount of accumulated metabolites. An example of the pharmacokinetic information output calculation formula will be described later. The part information includes, for example, “stomach”, “duodenum”, “jejunum”, “ileum”, “large intestine”, and the like. The state information includes, for example, the drug dissolution state, dissociation state, drug absorption, metabolism, excretion rates, excretion amount, metabolite amount, absorption amount, and the like. The arithmetic expression storage unit 1105 is preferably a non-volatile recording medium (including a hard disk or a non-rewritable optical disk), but can also be realized by a volatile recording medium.

 The calculation execution unit 1106 passes the drug information received by the drug information reception unit 1102 and the parameter having the biological information received by the biological information reception unit 1104 to the pharmacokinetic information output calculation formula of the calculation formula storage unit 1105. Execute pharmacokinetic information output calculation formula. The arithmetic execution unit 1106 can usually also realize an MPU, a memory and the like. The processing procedure of the arithmetic execution unit 1106 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

 The output unit 1107 outputs pharmacokinetic information that is information based on the execution result of the calculation execution unit 1106. The output here is normally a transmission to the control device 13. However, when the simulation device 11 operates alone, the output includes display on a display, printing on a printer, sound output, transmission to an external device, and the like. The output unit 1107 can be realized by, for example, a wireless or wired communication unit. The output unit 1107 can be realized by, for example, output device driver software, or output device driver software and an output device.

 Second instruction receiving unit 1201 receives an instruction to transmit biological information from control device 13. The second instruction receiving unit 1201 can be usually realized by a wireless or wired communication means.

[0019] The functional element information storage unit 1202 is a simulation realizing program for simulating a function element identifier for identifying a function of a molecule, an intracellular organelle, a cell, a tissue, or an organ that is an element constituting an organism, and the function. Stores one or more pieces of functional element information with The functional element information may include a functional element identifier, a program identifier for identifying a simulation realization program, and a simulation realization program. Further, the functional element information may include a functional element identifier and two or more simulation realization programs. The function element identifier may be anything as long as it is information for identifying the function. Stain The description language and format of the urease realization program are not limited. In other words, the simulation realization program may be an execution format, a library format, or a program function. Among the one or more simulation realization programs, there is also a program that also outputs the simulation results. Here, output is a concept including display on a display, printing on a printer, sound output, transmission to an external device, storage on a recording medium, and the like. The functional element information storage unit 1202 is preferably a non-volatile recording medium, but can also be realized by a volatile recording medium.

 [0020] The static structure management unit 1203 has a component identifier that identifies a biological component or individual that is an intracellular organelle, cell, tissue, organ, and a function of the biological component that is identified by the component identifier. Corresponds to one or more functional element identifiers necessary for realization. The static structure management unit 1203 is preferably a nonvolatile recording medium, but can also be realized by a volatile recording medium.

 [0021] The parameter management unit 1204 holds parameter information having a component identifier and one or more parameters necessary for realizing the function of the component of the organism identified by the component identifier. The parameter management unit 1204 can also be realized by a force volatile recording medium, which is preferably a non-volatile recording medium.

 [0022] The simulation command receiving unit 1205 receives a simulation command having a component identifier for identifying a biological component or individual to be simulated. Any method may be used for inputting the simulation command, such as a numeric keypad, keyboard, mouse or menu screen. The simulation command receiving unit 1205 can be realized by a device driver for input means such as a numeric keypad or a keyboard, or control software for a menu screen.

The functional element identifier acquisition unit 1206 acquires, from the static structure management unit 1203, one or more functional element identifiers that are associated with the component element identifiers included in the simulation command received by the simulation command reception unit 1205. The functional element identifier acquisition unit 1206 can usually also be implemented with an MPU or memory power. The processing procedure for the functional element identifier acquisition unit 1206 to acquire one or more functional element identifiers is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, with hardware (dedicated circuit) It may be realized.

 [0024] The parameter acquisition unit 1207 acquires from the parameter management unit 1204 one or more parameters corresponding to the constituent element identifiers included in the simulation command received by the simulation command reception unit 1205. The parameter acquisition unit 1207 can usually be realized from an MPU, a memory, or the like. The processing procedure for the parameter acquisition unit 1207 to acquire one or more parameters is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

 The execution unit 1208 passes a part or all of the parameters acquired by the meter acquisition unit 1207 to the simulation realization program paired with the functional element identifier acquired by the functional element identifier acquisition unit 1206, and performs the simulation. Run the realization program. The simulation information program paired with the functional element identifier acquired by the functional element identifier acquisition unit 1206 can also determine the management information power in the functional element information storage unit 1202. The execution unit 1 208 can usually also realize an MPU, a memory and the like. The processing procedure of the execution unit 1208 is usually realized by software, and the software is recorded on a recording medium such as a ROM. However, it may be realized by hardware (dedicated circuit).

 The biological information transmission unit 1209 transmits the biological information acquired by executing the simulation in the execution unit 1208 to the control device 13. The biological information transmission unit 1209 can be realized by a wireless or wired communication means.

 The cell function management means 12031 manages the correspondence between the cell identifier for identifying the cell or tissue of the organism and the function identifier!

 [0026] The organ cell management means 12032 manages the correspondence between an organ identifier for identifying an organ or an organ and a cell identifier. The cell function management means 12031 and the organ cell management means 120 32 are preferably non-volatile recording media, but can also be realized by volatile recording media.

 The instruction unit 1301 sends a simulation start instruction to the simulation apparatus 11 and instructs the cell simulation apparatus 12 to send biological information. The instruction unit 1301 can be realized by, for example, a wireless or wired communication unit.

The biological information acquisition instruction receiving unit 1302 acquires biological information from the simulation apparatus 11. The instruction is accepted. The reception is, for example, reception. The biological information acquisition instruction receiving unit 1302 can be realized by, for example, a wireless or wired communication unit.

The biological information acquisition unit 1303 acquires biological information from the cell simulation device 12 in response to an instruction to send biological information. The biological information acquisition unit 1303 receives biological information, for example. The biological information acquisition unit 1303 can be realized by, for example, a wireless or wired communication unit.

 The biometric information adding unit 1304 sends the biometric information acquired by the biometric information acquiring unit 1303 to the simulation apparatus 11. Sending is transmission, for example. However, the sending may be an operation for giving biological information to the simulation apparatus 11. The biometric information providing unit 1304 can be realized by, for example, a wireless or wired communication unit.

 The execution result acquisition unit 1305 acquires pharmacokinetic information that is a simulation execution result from the simulation apparatus 11. Acquisition is, for example, reception. The execution result acquisition unit 1 305 can be realized by, for example, a wireless or wired communication unit.

 The execution result display unit 1306 displays the pharmacokinetic information of the drug acquired by the execution result acquisition unit 1305. The manner in which the execution result display unit 1306 displays the pharmacokinetic information is not limited. The execution result display unit 1306 may display the pharmacokinetic information in a graph, a numerical string and a character string, or a moving image (such as an animation). The execution result display unit 1306 may or may not include a display. Execution Result Display Unit 1306 can be realized by display driver software or display driver software and a display.

 Hereinafter, the operation of the information processing system will be described. First, the operation of the simulation apparatus 11 will be described using the flowchart of FIG.

 (Step S201) The instruction receiving unit 1101 determines whether or not a start instruction that is an instruction to start a drug absorption or Z and excretion simulation has been received. If the start instruction is accepted, the process goes to step S202. If the start instruction is not accepted, the process returns to step S201.

[0034] (Step S202) The drug information receiving unit 1102 determines whether or not it has received the drug information, which is information on the drug to be simulated. If you accept drug information, Go to step S203, and if drug information is not accepted, return to step S202.

(Step S203) The biological information receiving unit 1104 determines whether or not biological information related to biological information has been received. If biometric information is accepted, the process goes to step S204, and if biometric information is not accepted, the process returns to step S203.

 (Step S204) The calculation execution unit 1106 reads the pharmacokinetic information output calculation formula from the calculation formula storage unit 1105.

 (Step S205) The calculation execution unit 1106 executes the pharmacokinetic information output calculation formula acquired in step S204 using the drug information received in step S202 and the biological information received in step S203 as parameters.

 (Step S206) The output unit 1107 outputs pharmacokinetic information which is information on the execution result of the calculation execution unit 1106.

 (Step S207) The biological information acquisition instruction unit 1103 transmits a biological information acquisition instruction to the control device 13 to indicate acquisition of biological information. Note that the simulation apparatus 11 may acquire biological information from the control apparatus 13 without transmitting the biological information acquisition instruction to the control apparatus 13. In such a case, the cell simulation device 12 voluntarily transmits the biological information to the control device 13, or the control device 13 voluntarily acquires the biological information from the cell simulation device 12. In addition, it is desirable that the timing for acquiring the biological information from the control device 13 is periodic, but it is not essential to be periodic.

 In the flowchart of FIG. 2, the process ends when the power is turned off or the process is terminated.

 Next, the operation of the cell simulation device 12 will be described using the flowchart of FIG.

 (Step S301) The simulation command receiving unit 1205 determines whether or not a simulation command having a component identifier (here, for example, an organ identifier) has been received. If a simulation command is accepted, the process proceeds to step S302. If a simulation command is not accepted, the process proceeds to step S314. Here, the simulation command is a simulation start instruction received from the control device 13.

(Step S302) An organ identifier included in the simulation command is acquired. (Step S303) The functional element identifier acquisition unit 1206 acquires one or more cell identifiers corresponding to the organ identifier acquired in step S302.

 (Step S304) 1 is assigned to the counter i.

(Step S305) The execution unit 1208 determines whether or not the i-th cell identifier is present in the cell identifier acquired in step S303. If the cell identifier of the cell exists, the process goes to step S306, and if the i-th cell identifier does not exist, the process ends. Needless to say, even if the flowchart in Fig. 3 is completed, the simulation result output by the simulation realization program may continue.

 (Step S306) The functional element identifier acquisition unit 1206 acquires one or more functional element identifiers corresponding to the i-th cell identifier.

 (Step S307) 1 is assigned to the counter j.

(Step S308) The execution unit 1208 determines whether or not the j-th functional element identifier exists in the functional element identifier acquired in step S306. If the jth functional element identifier exists, the process goes to step S309, and if the jth functional element identifier does not exist, the process jumps to step S313.

 (Step S309) The execution unit 1208 reads the simulation realization program corresponding to the j-th functional element identifier from the functional element information storage unit 1202.

[0041] (Step S310) The parameter acquisition unit 1207 receives one or more parameters corresponding to the organ identifier included in the simulation command received by the simulation command receiving unit 1205.

Obtained from the parameter management unit 1204.

(Step S311) The execution unit 1208 passes the one or more parameters acquired in step S310 to the simulation implementation program acquired in step S309, and executes the simulation implementation program.

 (Step S312) The counter j is incremented by one. Return to step S308.

 (Step S313) The counter i is incremented by one. Return to step S305.

(Step S 314) Second instruction accepting unit 1201 determines whether or not an instruction to transmit biometric information from control device 13 has been accepted. If an instruction to transmit biometric information is accepted, the process goes to step S315. If an instruction to transmit biometric information is not accepted, the process returns to step S301. (Step S315) The biological information transmitting unit 1209 acquires biological information necessary for drug absorption or Z and excretion simulation from the biological information obtained by executing the simulation in the execution unit 1208. For example, information indicating biological information necessary for simulation of drug absorption or Z and excretion is included in an instruction to transmit biological information.

 (Step S316) The biological information transmitting unit 1209 transmits the biological information acquired in Step S315 to the control device 13. Return to step S301.

 In the flowchart of FIG. 3, when two or more simulation realization programs are executed, the execution order may be determined or may be arbitrary. In addition, the simulation realization program may output the simulation result periodically or at an appropriate timing as time elapses beyond just an instruction from the control device 13, for example.

 Furthermore, the function of the cell simulation device 12 used in the information processing system in the present embodiment is a simulation function for cells, mainly epithelial cells. The epithelial cell simulation function is performed, for example, by executing an arithmetic expression (model) described in Non-Patent Document 2, Non-Patent Document 3, and Non-Patent Document 4 described above.

 [0047] Non-Patent Document 2 discloses an arithmetic expression capable of calculating membrane potential, ion flow, water flow, and cell volume. Non-Patent Document 3 discloses an arithmetic expression capable of calculating transporters involved in ion transport. Non-Patent Document 4 discloses a technique for improving a glucose transporter. For example, necessary calculations and operations in the cell simulation device 12 can be realized from these three non-patent documents. Therefore, a detailed description of cell simulation is omitted. Next, the operation of the control device 13 will be described using the flowchart of FIG.

 (Step S 401) The instruction unit 1301 sends a simulation start instruction to the simulation apparatus 11 and the cell simulation apparatus 12. Normally, the simulations of the simulation apparatus 11 and the cell simulation apparatus 12 are synchronized, but there are cases where both may operate without synchronization.

(Step S402) The biometric information acquisition instruction receiving unit 1302 starts from the simulation apparatus 11. It is determined whether or not the force of receiving an instruction to acquire biometric information is received. If the biometric information acquisition instruction is accepted, the process proceeds to step S403, and if the biometric information acquisition instruction is not accepted, the process jumps to step S406.

 (Step S403) The biological information acquisition unit 1303 gives an instruction to send the biological information to the cell simulation device 12 in accordance with the biological information acquisition instruction in step S402.

 (Step S404) The biological information acquisition unit 1303 acquires biological information from the cell simulation device 12 in response to the instruction to send biological information in step S403.

 (Step S405) The biometric information adding unit 1304 sends the biometric information acquired in step S404 to the simulation apparatus 11. Return to step S402.

(Step S 406) The execution result acquisition unit 1305 determines whether or not it has acquired the pharmacokinetic information, which is the execution result of the simulation, from the simulation apparatus 11. If pharmacokinetic information is acquired, the process goes to step S407, and if pharmacokinetic information is not acquired, the process returns to step S402.

 (Step S407) The execution result display unit 1306 displays the pharmacokinetic information of the drug acquired in step S406. Return to step S402.

 In the flowchart of FIG. 4, the process ends when the power is turned off or the process is terminated.

 [0051] In the above block diagram and flowchart, the biological information is notified from the cell simulation device 12 to the simulation device 11 via the control device 13. However, the biological information may be directly notified from the cell simulation device 12 to the simulation device 11.

 Hereinafter, a specific operation of the information processing system in the present embodiment will be described. The concept of the operation of the information processing system will be described with reference to FIG. The cell simulation device 12 of the information processing system is a gastrointestinal epithelial cell simulation device that performs simulation of gastrointestinal epithelial cells.

First, the cell simulation device 12 receives information on functional abnormalities such as pathological changes and congenital abnormalities from the outside. It also calculates changes in biological information such as transporter drive, ion channel opening and closing, permeation pressure change, hydrostatic pressure change, potential change, and water ion movement. Get out and get. Examples of information such as pathological changes accepted by the cell simulation device 12 include information on SGLT1 activity reduction due to virus infection. When the cell simulation apparatus 12 receives information on SGLT1 activity decrease due to such virus infection, the main biological information change is diarrhea and a decrease in water absorption rate. The decrease in water absorption rate is the decrease in intracellular Na concentration.

 Next, the value of the variable is transferred from the cell simulation device 12 to the control device 13. Variable values include pH, membrane potential, water absorption rate, and cell volume. The values of variables such as pH, membrane potential, water absorption rate, and cell volume are also the above-described biological information. Further, the variable value is passed from the control device 13 to the simulation device 11.

 [0055] The biological information receiving unit 1104 of the simulation apparatus 11 receives biological information such as pH, membrane potential, water absorption rate, and cell volume. Then, the calculation execution unit 1106 reads out the stored pharmacokinetic information output calculation formula. Then, the received biological information and pre-stored drug information are given to the read pharmacokinetic information output calculation formula, and the drug behavior information output calculation formula is executed. By executing the pharmacokinetic information output calculation formula, the movement of the drug in the digestive tract, the dissolution of the drug, the dissociation due to the pH change of the drug, the absorption of the drug by transcellular permeation, the absorption of the drug by permeation of the cell gap, Information on liver metabolism, renal excretion of drugs, drug transport by P-glycoprotein, and first-pass metabolism (by liver, small intestine, etc.). In such cases, drug information includes solubility, dissolution rate constant, membrane permeability coefficient, acid dissociation constant (pKa), in vitro liver metabolic rate, plasma protein binding rate, animal data, and expected human renal clearance and distribution. There are volume values, Michaelis-Menten constant for P-glycoprotein (Km), and maximum transport rate (Vmax).

 [0056] Then, the output unit 1107 of the simulation apparatus 11 outputs information based on the execution result of the pharmacokinetic information output arithmetic expression. Information based on this execution result is pharmacokinetic information. Examples of pharmacokinetic information include drug absorption rate, drug metabolism rate, drug urinary excretion rate, drug first-pass metabolic rate, drug blood concentration, drug absorption, drug accumulation renal excretion And cumulative metabolic rate of drugs.

[0057] In addition, in the above description, the force cell simulation device 12 described in detail stops the simulation (calculation) when the value of the output variable reaches an equilibrium state, and finally obtains the value. Is held. On the other hand, the simulation device 11 continues to calculate pharmacokinetic information while acquiring biological information from the cell simulation device 12 regardless of the state of operation of the cell simulation device 12 (operating or stopped). The execution result of the pharmacokinetic information output calculation formula and the output pharmacokinetic information may be the same or different.

 Next, specific simulations and results will be further described below using two specific examples.

[0058] [Specific Example 1]

 The cell simulation device 12 receives, for example, information indicating that SGLT1 activity is reduced due to virus infection and an organ identifier or cell identifier to be simulated. Then, the cell simulation device 12 reads the simulation identifier corresponding to the cell identifier included in the organ identified by the organ identifier or the received cell identifier. The cell simulation device 12 implements the program. Then, since SGLT1 activity falls, the cell simulation apparatus 12 calculates information that the inflow of Na and G1 ucose into cells is suppressed.

[0059] Next, the cell simulation device 12 calculates a simulation result in which the difference in the concentration in the extinction lumen with respect to the intracellular concentrations of Na and Glucose becomes larger due to the decrease in SGLT1 activity. This means that an osmotic pressure difference between the lumen and the cell is larger than that in the normal state. This also means that the flow of water due to the osmotic pressure difference (from low to high osmotic pressure) becomes smaller and water accumulates in the lumen. Accumulation of water in the lumen can also cause diarrhea. Furthermore, the cell simulation device 12 calculates the inflow speed of water from the inside of the lumen. The inflow here means inflow into cells and inflow into cell gaps. The cell simulation device 12 calculates a simulation result that both the inflow rate into the cell and the inflow rate into the cell gap decrease in a situation where the concentrations of Na and Glucose in the lumen increase. Fig. 6 shows a conceptual diagram of the inflow of water into the cell and the inflow of water into the cell gap.

Next, the instruction receiving unit 1101 of the simulation apparatus 11 receives a simulation start instruction from the control apparatus 13. The drug information receiving unit 1102 stores the stored drug. Drug information such as solubility (5.0 here) and dissolution rate constant.

 Next, the living body information receiving unit 1104 of the simulation apparatus 11 passes information about the inflow speed of water into the cell and the inflow speed of water into the cell gap from the cell simulation apparatus 12 via the control apparatus 13, and the membrane. Biological information such as potential is acquired.

Then, the calculation execution unit 1106 of the simulation apparatus 11 reads the pharmacokinetic information output calculation formula shown in FIG. 7 from the calculation formula storage unit 1105 and executes it. Pharmacokinetic information output The calculation formula is, for example, a differential equation. In FIG. 7, n means the left force n of the compartment group in FIG. 19, and the upper, middle, and lower compartments respectively have drug amounts of Mn, Sn, and En. In addition, the arrows between the compartments each have the value of the drug movement speed calculated in FIG. 7 and FIG. First, the simulation apparatus 11 executes the pharmacokinetic information output calculation formula of FIG. Then, the simulation apparatus 11 obtains information on the time change of the solid drug amount. More specifically, the operation execution unit 1106 calculates “dM = (Κ · Μ _ -Κ · Μ -dissolution) X dt” at a predetermined interval (eg, 0.1 second), and every dt Calculate the amount of solid drug (Mn) in the nth compartment. In the pharmacokinetic information output calculation formula of FIG. 7 ( _a ), “dM” is the amount of increase in the solid drug amount (Mn). K is a moving speed constant of the lumen contents, and is a constant stored in advance in the arithmetic expression storage unit 1105 (recording medium). “Dissolution” is the rate of elution by diffusion and can be calculated by the formula in FIG. It goes without saying that the arithmetic execution unit 1106 reads constants (K and the like) from the arithmetic expression storage unit 1105 together with the arithmetic expression and executes the arithmetic expression. Note that, when the calculation execution unit 1106 executes a differential equation, the calculation of dt at a predetermined interval (for example, 0.1 second) is the same in the execution of other differential equations. Since it is technology · processing, detailed explanation is omitted. From FIG. 7 (a), the calculation execution unit 1106 calculates a solid drug amount (Mn) by executing a function using the movement rate constant of the luminal contents and the dissolution rate as parameters. Further, the calculation execution unit 1106 is an increase function using the moving rate constant of the lumen contents as a parameter, and calculates the solid drug amount (Mn) by executing a decrease function using the dissolution rate as a parameter. That is, the calculation formula for calculating the solid drug amount (Mn) by the calculation execution unit 1106 is not limited to FIG. 7 (a).

Next, the calculation execution unit 1106 of the simulation apparatus 11 receives the calculation formula storage unit 1105 from FIG. Read and execute the pharmacokinetic information output calculation formula in (b). Then, the simulation apparatus 11 obtains information on the time change of the dissolved drug amount. In the pharmacokinetic information output formula of Fig. 7 (b), the calculated "S" is the amount of liquid drug in the eleventh gastrointestinal compartment, and "V" is the volume of water. Obtained by executing the first differential equation. “C” is the drug concentration in the nth gastrointestinal compartment, and is obtained by executing the second differential equation in FIG. 7 (b). Flux (para) is the rate at which the luminal side force is transported into the cell space by diffusion and / or volumetric flow transport based on the electrochemical potential gradient. Calculated. Flux (trans) is the rate at which the drug is transported into the luminal force cell by diffusion and / or active transport based on the electrochemical potential gradient. Calculated by execution. P-gp is a drug return rate by P glycoprotein, and is calculated by, for example, constants, and V stored in the arithmetic expression storage unit 1105 in advance. Calculation

 m max

When executing the pharmacokinetic information output calculation formula of FIG. 7 (b), the execution section 1106 reads P-gp from the calculation formula storage section 1105 and gives it to the pharmacokinetic information output calculation formula. waterflu X is the water absorption rate (intracellular, cell membrane), generated by the cell simulator device 12, sent via the control device 13, and stored in the arithmetic expression storage unit 1105 in advance as a variable value. is there. When executing the pharmacokinetic information output arithmetic expression of FIG. 7B, the arithmetic execution unit 1106 reads out the waterflux from the arithmetic expression storage unit 1105 and gives it to the pharmacokinetic information output arithmetic expression. From Fig. 7 (b), the calculation execution unit 1106 shows the volume of water, dissolution rate, drug cell void root velocity (flux (para)), drug intracellular route velocity (flux (trans)), P glycoprotein I that drug return speed (P- _g p), the absorption rate of water by (intracellular, cell membranes) (waterflux) function to parameters one motor, and calculates the liquid amount of drug and drug concentrations. The calculation execution unit 1106 is an increasing function using the dissolution rate and the drug return rate (P—gp) by the P-glycoprotein as parameters, and the drug cell gap root velocity (flux (para)), the drug intracellular route The liquid drug amount (Sn) and drug concentration (Cn) are calculated using a decreasing function with the velocity (flux (tran s)) as a parameter. That is, the calculation formula for calculating the liquid drug amount (Sn) and the drug concentration (Cn) by the calculation execution unit 1106 is not limited to FIG. 7 (b).

Next, the calculation execution unit 1106 of the simulation apparatus 11 receives the calculation formula storage unit 1105 from FIG. Read and execute the pharmacokinetic information output calculation formula of (c). Then, the simulation device 11 obtains information on the time change of the drug amount in the epithelial cells. Pharmacokinetic information in Fig. 7 (c) In the calculation formula, “E” is the amount of drug in the epithelial cells. The absorption is the absorption rate from the epithelial cells, which is the same as “absorption” in FIG. 8, and is calculated by the arithmetic expression “absorption”. Metabolism is the metabolic rate in the digestive tract, which is the same as “metabolic-rate” in FIG. 8, and is calculated by the “metabolic-rate” equation in FIG. “Ce” is the intracellular drug concentration of the nth epithelial cell compartment, and “Ve” is the cell volume. From Fig. 7 (c), the operation execution unit 1106 shows that the intracellular route speed of the drug (fl ux (trans)), the absorption rate from the epithelial cells, the metabolic rate in the digestive tract, the drug return rate by P glycoprotein (P— The amount of drug in the epithelial cells is calculated by executing a function that calculates gp). The calculation execution unit 1106 is an increasing function with the intracellular route velocity (flux (trans)) of the drug as a parameter, the absorption rate from the epithelial cells, the metabolic rate in the digestive tract, the drug return rate by the P-glycoprotein ( The amount of drug (En) in the epidermal cells is calculated by executing a decreasing function with P-gp) as a parameter. That is, the calculation formula for calculating the drug amount (En) in the epithelial cells by the calculation execution unit 1106 is not limited to FIG. 7 (c).

 Next, the calculation execution unit 1106 of the simulation apparatus 11 receives the calculation formula storage unit 1105 from FIG.

(d) The pharmacokinetic information output calculation formula is executed. Then, the simulation device 11 obtains information on the time change of the drug amount in the plasma. In the pharmacokinetic information output calculation formula in FIG. 7 (d), “C” to be calculated is the plasma drug concentration. F is the liver availability

 plasma h

1 (the ratio of the drug that has not been metabolized after the first pass through the liver), and the metabolic rate force obtained from the in vitro experiment of the drug is also calculated by the disparsion model equation. On the other hand, the rate at which the drug is metabolized by the first pass of the liver is expressed as absorption-rate '(1-Fh), and is integrated over time to calculate the cumulative first pass metabolic rate of the liver. CLh is liver clearance, CLr is renal clearance, and Vd is a distribution volume (drug), which are constants stored in advance in the arithmetic expression storage unit 1105. Liver metabolic rate and urinary excretion rate are CLh 'C

 plasma

, CLr-C and integrated over time, cumulative liver metabolism and cumulative urinary excretion

 plasma

Calculated. When executing the pharmacokinetic information output calculation formula in FIG. 7 (d), the calculation execution unit 1106 reads out each constant from the calculation formula storage unit 1105 and outputs the pharmacokinetic information output calculation formula. Give to the expression. From FIG. 7 (d), the operation execution unit 1106 shows that the liver availability is the highest (F), the epithelial cell h

Absorption rate into the blood (absorption), drug cell root velocity (flux (para)), drug elimination rate due to liver clearance (CLh), urinary excretion rate due to renal clearance (CLr), distribution volume (Vd ) Is used as a parameter to calculate the plasma drug concentration (C) plasma. Arithmetic execution unit 1106 has the highest liver availability (F), blood from the epithelial cell h

Absorption, drug space gap velocity (flux (para)) force increase function, liver clearance (CLh) drug disappearance rate, renal clearance (CLr) urinary excretion rate force decrease function The amount of drug in the body is calculated by performing the above, and the drug concentration in plasma (C) is calculated by dividing by the distribution volume (Vd). In other words, the calculation execution unit 1106

The calculation formula for calculating the drug concentration (C) is not limited to FIG. 7 (d).

 plasma

 Fig. 8 shows the equation for calculating the variables (double line values) in Fig. 7. In Fig. 8, the expression force enclosed by a rectangle is an important expression for changing the simulation results.

 In FIG. 7, the underlined variables (waterflux, Ve) are variables whose values are given from the cell simulation device 12 to the simulation device 11 via the control device 13.

 In FIG. 8, dissolution is the rate of dissolution by diffusion. Flux (para) is the rate at which the drug is transported by either diffusion or volumetric flow based on the electrochemical potential gradient, but not by any deviation. Flux (trans) is the rate at which a drug is transported by diffusion and / or active transport based on an electrochemical potential gradient. Absorption-rate is the rate of absorption from epithelial cells and cell space. metabolic -rate is the metabolic rate expressed by enzyme reaction theory. P is paracellular

 P

 The membrane permeability of route, pKa is the acid 'base dissociation constant. Also, in FIG. 8, all the calculation formulas including pKa show the case of a basic drug, and in the case of an acidic drug, it is based on the Henderson-Hasselbach formula at the bottom of FIG. — The term of pH is (pH -pKa).

Then, during the simulation of drug absorption or Z excretion of the simulation device 11, the cell simulation device 12 controls the changing biological information shown in FIG. 9 and FIG. 3 to send to simulation device 11. The changes in the biological information in FIGS. 9 and 10 are changes in the biological information after 60 minutes have elapsed since the start of the drug simulation of the simulation apparatus 11. In other words, “0” on the horizontal axis (time) in FIG. 9 is when 60 minutes have elapsed since the start of the drug simulation.

 [0062] In Fig. 9, (a) is a graph showing the change in pH value, which is one of the biological information. The vertical axis represents pH and the horizontal axis represents the time from 60 minutes after SGLTl activity begins to decrease ( min). Similarly, Fig. 9 (b) is a graph showing the time course (60-120min) of SGLT1 activity molGlcZsec), and Fig. 9 (c) shows the potential difference between the luminal cell surface and the intercellular space, that is, the membrane. It is a graph which shows the time transition (60-120min) of electric potential (mV). Figure 10 is a graph showing changes in the water flow rate, with the horizontal axis representing the time (min) after 60 minutes when SGLT1 activity begins to decrease and the vertical axis representing the water flow rate (mlZsec). Yes. The upper line in Fig. 10 is a graph showing changes in the water flow rate in both the intracellular route and the cell space route. The lower line in Fig. 10 is a graph showing the change in the water flow rate of the cell space route.

 The simulation apparatus 11 receives the biological information shown in FIGS. 9 and 10 from the cell simulation apparatus 12 via the control apparatus 13 at any time (regularly or irregularly). However, the configuration may be such that the simulation apparatus 11 receives the biological information only when the biological information has changed.

[0064] Then, the simulation apparatus 11 outputs a change in the moving speed of the drug shown in Fig. 11 (b). In Fig. 11 (a) and (b), the horizontal axis is the elapsed time (min) after taking the drug, and the vertical axis is the drug movement speed (gZmin). Here, the display of FIG. 11B is performed by the control device 13. Needless to say, the control device 13 acquires the pharmacokinetic information necessary for the graph display of FIG. 11B from the simulation device 11. In addition, the graph in Fig. 11 (b) shows the change in drug movement speed during virus infection. The change in drug movement speed during normal operation is shown in the graph in Fig. 11 (a). In the cell simulation device 12, information indicating that SGL T1 activity decreases due to virus infection is not accepted! / If (normal), the simulation device 11 uses the pharmacokinetics constituting the graph shown in FIG. The information is output, and the control device 13 displays the graph shown in FIG. 11 (a). The graphs (1) and (3) in Fig. 11 show the drug absorption rate. The graphs (2) and (4) in Fig. 11 show the urinary excretion rate of the drug. [0065] Further, the simulation apparatus 11 outputs a change in the amount of drug shown in FIG. 12 (b). In Fig. 12 (a) and (b), the horizontal axis is the elapsed time (min) after taking the drug, and the vertical axis is the drug amount (µg). Here, the display of FIG. 12 (b) is performed by the control device 13. Needless to say, the control device 13 acquires the pharmacokinetic information necessary for the graph display in FIG. 12 (b) from the simulation device 11. In addition, the graph in FIG. 12 (b) shows the change in drug amount during virus infection. The change in drug amount at normal time is shown in the graph in FIG. 12 (a). If the cell simulation device 12 does not accept information indicating that the SGLT1 activity is reduced due to virus infection (normal), the simulation device 11 outputs the pharmacokinetic information constituting the graph shown in Fig. 12 (a). Then, the control device 13 displays the graph shown in FIG. The graphs (1) and (5) in Fig. 12 show the amount of drug in the circulating blood, (2) and (6) show the cumulative urinary excretion, and (3) and (7) show the cumulative liver metabolism of the circulating blood drug. , (4) and (8) show cumulative first-pass metabolism.

 [0066] FIG. 12 (b) shows the following. In other words, during viral infection, the amount of drug transported by volume flow decreases due to the inflow of water from the lumen into the cell gap. In addition, since water accumulates in the lumen, the drug concentration in the lumen, which is the driving force for drug diffusion, decreases, and the amount of drug that diffuses into cells and cell gaps also decreases. For the above reasons, the inflow rate (absorption rate) of the drug decreases and the absorption amount also decreases. Note that the moving speed of the drug in the intracellular route in FIG. 6 mainly depends on the concentration gradient. On the other hand, the moving speed of the drug in the cell space route depends greatly on the water flow speed (Waterflux in the following Equation 1). The intercellular route is dissociated, dissociated, dissociated, and the drug molecules in the dissociated state also pass through. However, a drug that is easily dissociated in the intestinal pH region cannot be permeated through the intracellular route. The ratio is large and the contribution through the intercellular space route is relatively high, and it is easily affected by the inflow rate of water. In addition, the concentration gradient between the lumen and the cell (lumen> intracellular) becomes smaller and the absorption rate decreases. At this time, it is considered that the effect is greater when the solubility of the drug is higher than when the solubility of the drug is low.

[Number 1]

 The first term on the right side of Equation 1 is the inflow rate of the drug based on the constant field theory. In addition, the second term on the right side in the above formula is the inflow rate of the drug based on the drug concentration difference between the digestive tract cavity and the cell gap. Furthermore, the third term on the right side of the mathematical formula is the inflow rate of the drug that flows in along with the flow of water.

 In addition, the changes during infection in Figure 9, Figure 10, and Figure 11 are largely due to the change in the calculation result in the third term of Equation 1.

 [Specific example 2]

 Concrete example 2 outputs the simulation results in a simulation system set to give water to the lumen at a constant rate by the secretion of saliva, compared to the experimental environment in example 1.

This setting is done by giving the formula when n = 1 in Fig. 7 (a) as shown in formula 2. In Equation 2, “salivary flow” is the salivary secretion rate. The arithmetic execution unit 1106 reads the value of “salivary flow” stored in the arithmetic expression storage unit 1105 and executes the arithmetic expression.

[Equation 2]

^ ^Τ --salivary flow one K _t -V _x one waterflux

 dt

In Specific Example 2, as in Specific Example 1, the cell simulation device 12 For example, when SGLT1 activity is reduced due to virus infection (SGLT1 activity is reduced from 100% to 10% in 30 minutes for 40 minutes after taking the drug) and the organ identifier or cell to be simulated Accept identifiers. Then, the cell simulation device 12 reads a simulation identifier corresponding to the cell identifier included in the organ identified by the organ identifier or the received cell identifier. Then, the cell simulation device 12 realizes the program. Then, since the SGLT1 activity decreases, the cell simulation device 12 calculates information that suppresses the inflow of Na and Glucose into the cell.

 In Example 2, compared to the case in Example 1, increase the values of Kt, Pp and solubility, and decrease the values of pKa and renal clearance!

 More specifically, the cell simulation apparatus 12 is a graph showing the time transition of pH value (vertical axis is pH, horizontal axis is elapsed time (min) after taking a drug), which is one of the biological information shown in FIG. Is generated and sent to the simulation device 11 via the control device 13. In addition, the cell simulation apparatus 12 shows a time chart of SGLT1 activity shown in FIG. 14 (the vertical axis is SGL T1 transport activity (μmolGlc / sec), and the horizontal axis is the elapsed time (min) after taking the drug). A value is generated and sent to the simulation device 11 via the control device 13. In addition, the cell simulation device 12 shows the time transition of the potential difference between the luminal cell surface and the interstitial space shown in FIG. 15 (the vertical axis is the potential (mV), and the horizontal axis is the elapsed time after taking the drug (min)). A value of the indicated draft is generated and sent to the simulation device 11 via the control device 13. In addition, the cell simulation device 12 generates a graph value indicating the time transition of the water flow rate of both the intracellular route and the cell space route shown in (1) of FIG. 16, and the simulation is performed via the control device 13. Send to device 11. The vertical axis in Fig. 16 is the water flow rate (mlZsec), and the horizontal axis is the elapsed time (min) after taking the drug. Further, the cell simulation device 12 generates a graph value indicating the time transition of the flow rate of the water in the cell gap route shown in (2) of FIG. 16 and sends it to the simulation device 11 via the control device 13.

That is, the simulation apparatus 11 receives the biological information shown in FIGS. 13 to 16 from the cell simulation apparatus 12 via the control apparatus 13 at any time (regularly or irregularly). Note that the simulation device 11 performs simulation only when there is a change in biological information. The device 11 may be configured to receive biological information! ,.

 Then, the simulation apparatus 11 outputs a graph showing the time transition of the drug moving speed shown in FIG. 17 (al). The vertical axis in FIG. 17 is the drug movement speed (gZmin), and the horizontal axis is the elapsed time (min) after taking the drug. Further, the simulation apparatus 11 outputs a graph showing the time transition of the urinary excretion rate of the drug shown in FIG. 17 (bl).

 FIGS. 17 (al) and (bl) are graphs showing the time transition of the drug absorption rate and the time transition of the urinary excretion rate of the drug when SGLT1 is inhibited, respectively. On the other hand, FIGS. 17 (a2) and (b2) are graphs showing the time transition of the absorption rate of the drug and the time transition of the urinary excretion rate of the drug, respectively. FIGS. 17 (a2) and 17 (b2) are simulation results of the simulation apparatus 11 when various information generated by the cell simulation apparatus 12 and sent via the control apparatus 13 is normal.

 In addition, the simulation apparatus 11 outputs a graph showing the time transition of the amount of drug in the circulating blood shown in FIG. 18 (al). The vertical axis in FIG. 18 is the drug amount g), and the horizontal axis is the elapsed time (min) after taking the drug. In addition, the simulation apparatus 11 outputs a graph showing the time transition of the cumulative urinary excretion of the drug shown in FIG. 18 (bl). Furthermore, the simulation apparatus 11 outputs a graph showing the time transition of the cumulative liver metabolic rate of the circulating blood drug shown in FIG. 18 (d) and the time transition of the cumulative liver first-pass metabolic rate shown in FIG. 18 (dl). .

 Figures 18 (al), (bl), (cl), and (dl) show the time course of circulating drug amount, the time course of cumulative urinary excretion of drug, and the cumulative amount of circulating blood drug when SGLT1 is inhibited, respectively. 2 is a graph showing the time course of liver metabolism and cumulative first-pass metabolism of liver. On the other hand, Figure 18 (a2), (b2), (c2), and (d2) show the time course of the amount of drug in the circulating blood, the time course of the cumulative urinary excretion of the drug, 3 is a graph showing the time course of metabolic rate and cumulative hepatic first-pass metabolic rate. Fig. 18 (a2), (b2), (c2), and (d2) are the simulation results of the simulation device 11 when various information generated by the cell simulation device 12 and sent via the control device 13 is normal. .

As described above, according to the present embodiment, a simulation apparatus that simulates drug absorption or Z and excretion based on drug information that is information related to a drug to be simulated and biological information related to biological information, Drug absorption simulation It is possible to provide a simulation device that dynamically accepts biological information even while playing. Therefore, it is possible to simulate drug absorption or Z and excretion taking into account individual differences, biological (cell) stimulation before and after drug administration, or pathological changes, etc.

[0069] Further, according to the present embodiment, since the accuracy of cell simulation is high and the result of cell simulation can be used for simulation of drug absorption or z and excretion, drug absorption or Z and excretion, etc. The accuracy of simulation is extremely high.

 [0070] According to the present embodiment, the biological information is a force applied to the simulation device via the cell simulation device force control device, and the biological information is applied directly to the simulation device from the cell simulation device. good. In such a case, a control device is unnecessary. Therefore, the simulation device accepts biological information that is output from the cell simulation device that simulates the movement in the cell (acceptance here includes direct and indirect), and based on the biological information and drug information. A simulation apparatus that simulates drug absorption or Z and excretion, and that dynamically receives the biological information during the simulation.

[0071] Also, according to the present embodiment, the biological information is given to the cell simulation apparatus power simulation apparatus. However, in the present embodiment, the biological information is not necessarily given from the cell simulation device. In the present embodiment, the biological information may be given to the simulation apparatus dynamically. For example, the simulation apparatus may periodically display a panel for requesting input of biometric information to the user and accept input of biometric information from the user. When receiving an input of new biological information, the simulation apparatus performs a drug simulation using the biological information. Further, for example, the simulation apparatus may perform drug simulation by using a plurality of sets of biological information stored in advance while switching between simulations. Further, for example, biological information may be periodically received from an apparatus other than the cell simulation apparatus. In other words, the simulation apparatus according to the present embodiment is based on drug information that is information about a drug to be simulated and biological information about biological information. Accordingly, a simulation apparatus for simulating drug absorption or Z and excretion, which dynamically accepts the biological information during the simulation.

 [0072] In addition, the movement and function of the cell simulation device in the present embodiment are not limited to those described above. Biological information (eg, membrane potential, ion flow, water flow, cell volume, transporter involved in ion transport, etc.) that is information about cells, especially epithelial cells, etc. can be acquired. It is sufficient if the biological information can be used.

 [0073] Further, according to the present embodiment, the pharmacokinetic information is only the state information indicating the state of the drug, but may include region information indicating the region that absorbs the drug. In other words, the output result of the simulation device 11 may be information indicating what state force (drug absorption rate, amount of absorption, etc.) the drug is in any part (for example, stomach, duodenum, etc.). . Figure 19 shows a conceptual diagram of such simulation. In FIG. 19, parts such as “stomach”, “duodenum”, “jejunum”, “ileum” and “large intestine” are on the horizontal axis (horizontal line). In addition, the state of the drug or the existing layer is the vertical axis (vertical line). The drug state or existing layer is “solid state”, “dissolved state”, “epithelial cell”, “blood vessel”. “Solid state” means that the drug exists in the digestive tract cavity in a solid state, “dissolved state” means that the drug exists in the digestive tract cavity in a dissolved state, and “epithelial cell” means that the drug is in the epithelial cell. “Vessel” means that a drug is present in the blood vessel. In the “solid state”, “dissolved state”, and “epithelial cell” boxes, the amount of drug can be indicated. Moreover, the arrow of FIG. 19 shows the flow of the drug.

Furthermore, the processing in the present embodiment may be realized by software. This software may be distributed by software download or the like. In addition, this software may be recorded and distributed on a recording medium such as a CD-ROM. This also applies to other embodiments in this specification. The software that realizes the simulation device in the present embodiment is the following program. In other words, this program has a drug information receiving step for receiving drug information, which is information about a drug to be simulated, a biological information receiving step for receiving biological information about biological information, the drug information, Using the biological information as a parameter The pharmacokinetic information output calculation formula is passed to the stored pharmacokinetic information output calculation formula, and the pharmacokinetic information output calculation formula is executed, and the pharmacokinetic information that is information based on the execution result in the calculation execution step is output. This is a program for executing The drug information receiving step may be an operation of reading drug information.

 Furthermore, it is preferable that the program receives biological information, which is a result of cell simulation simulating movement in a cell, in the biological information receiving step.

 FIG. 20 shows the external appearance of a computer that executes the programs described in this specification and realizes the simulation apparatus of the various embodiments described above. The above-described embodiments can be realized by computer hardware and a computer program executed thereon. FIG. 20 is an overview diagram of the computer system 340, and FIG. 21 is a block diagram of the computer system 340.

 In FIG. 20, a computer system 340 includes a computer 341 including an FD (Flexible Disk) drive and a CD-ROM (Compact Disk Read Only Memory) drive, a keyboard 342, a mouse 343, and a monitor 344.

 In FIG. 21, in addition to the FD drive 3411 and the CD-ROM drive 3412, the computer 341 includes a CPU (Central Processing Unit) 3413, a bus 3414 connected to the CPU 3413, the CD-ROM drive 3412 and the FD drive 3411, and a boot. A ROM (Read-Only Memory) 3415 for storing programs such as up-programs and a RAM (Random) connected to the CPU 3413 for temporarily storing application program instructions and providing a temporary storage space Access Memory) 3416 and an application program, a system program, and a hard disk 3417 for storing data. Although not shown here, the computer 341 may further include a network card that provides connection to the LAN.

A program for causing the computer system 340 to execute the function of the simulation apparatus of the above-described embodiment is stored in the CD-ROM 3501 or FD 3502, inserted into the CD-ROM drive 3412 or FD drive 3411, and further stored in the hard disk 3417. May be forwarded. Instead, the program is executed via a network (not shown). It may be transmitted to the computer 341 and stored in the hard disk 3417. The program is loaded into RAM3416 when executed. The program may be loaded directly from CD-ROM3501, FD3502 or network.

 The program does not necessarily include an operating system (OS) or a third-party program that causes the computer 341 to execute the functions of the simulation apparatus according to the above-described embodiment. The program only needs to include an instruction part that calls an appropriate function (module) in a controlled manner and obtains a desired result. How the computer system 340 operates is well known and will not be described in detail.

 In each of the above embodiments, each process (each function) may be realized by centralized processing by a single device (system), or by distributed processing by a plurality of devices. It will be realized.

[0076] In the above program, the transmission step for transmitting information and the reception step for receiving information are performed by hardware, for example, a modem or an interface card in the transmission step. Does not include processing (processing that can only be done with software)! /.

 Further, the computer that executes this program may be a single computer or a plurality of computers. That is, centralized processing or distributed processing may be performed.

 Further, in each of the above embodiments, it goes without saying that two or more communication means existing in one apparatus may be physically realized by one medium.

 The present invention can be variously modified without being limited to the above-described embodiments, and it goes without saying that these are also included in the scope of the present invention.

 Industrial applicability

[0077] As described above, the simulation apparatus according to the present invention is a simulation of drug absorption or Z and excretion in consideration of individual differences, biological (cell) stimulation before or after drug administration, or pathological changes. It can be used for information processing equipment used for drug and food dynamics studies and toxicity studies.

Brief Description of Drawings FIG. 1 is a block diagram of a simulation apparatus according to an embodiment.

 FIG. 2 is a flowchart for explaining the operation of the simulation apparatus.

FIG. 3 is a flowchart for explaining the operation of the cell simulation apparatus.

FIG. 4 is a flowchart for explaining the operation of the control device.

 [Figure 5] Conceptual diagram of operation of the information processing system

 [Figure 6] Schematic diagram of water inflow into the cell and water inflow into the cell gap 圆 7] Diagram showing the pharmacokinetic information output calculation formula

 [Figure 8] Figure showing the pharmacokinetic information output formula

[9] Diagram showing changes in biometric information

[10] Diagram showing changes in biometric information

 [Fig. 11] Diagram showing an example of output of the simulation apparatus

 FIG. 12 is a diagram showing an example of output of the simulation apparatus

[13] Diagram showing changes in biometric information

[14] Diagram showing changes in biological information

[15] Diagram showing changes in biometric information

圆 16] Diagram showing changes in biological information

 FIG. 17 is a diagram showing an output example of the simulation apparatus

 FIG. 18 is a diagram showing an example of output of the simulation apparatus

 [Figure 19] Conceptual diagram of the simulation

 [Fig. 20] Overview of the computer system constituting the simulation apparatus. [Fig. 21] Block diagram of the computer constituting the simulation apparatus.

Claims

The scope of the claims

 [1] A simulation device for simulating drug absorption or Z and excretion based on drug information, which is information about a drug to be simulated, and biological information about biological information,

 A simulation apparatus that dynamically accepts the biological information while performing the simulation.

 [2] A simulation device that simulates absorption or Z and excretion of a drug, a drug information receiving unit that receives drug information that is information about the drug targeted for the simulation,

 A biological information receiving unit that receives biological information related to biological information more than once, and an arithmetic expression that outputs pharmacokinetic information that is information related to absorption or Z and excretion of the drug using drug information and biological information as parameters. Stores pharmacokinetic information output formulas!

 A calculation execution unit that passes the drug information received by the drug information reception unit and the biological information received by the biological information reception unit as parameters to the pharmacokinetic information output calculation formula, and executes the pharmacokinetic information output calculation formula; ,

 A simulation apparatus comprising: an output unit that outputs pharmacokinetic information that is information based on an execution result of the calculation execution unit.

[3] The biological information receiving unit receives biological information related to biological information before the start of the simulation and during the simulation,

 The calculation execution unit

 The drug information received by the drug information receiving unit and the biological information received by the biological information receiving unit during the simulation are passed as parameters to the pharmacokinetic information output calculation formula, and the pharmacokinetic information output calculation formula is executed. The simulation device according to claim 2 to be performed.

[4] The pharmacokinetic information is

It has at least site information indicating the site that absorbs the drug and status information indicating the state of the drug. The simulation device according to any one of claims 1 to 3.

[5] The biological information receiving unit

 5. The simulation apparatus according to claim 1, which receives biological information that is an output from a cell simulation apparatus that simulates movement in a cell.

[6] On the computer,

 A drug information receiving step for receiving drug information, which is information about a drug to be simulated;

 A biological information receiving step for receiving biological information related to biological information more than once, the drug information, and passing the biological information as a parameter to a stored pharmacokinetic information output arithmetic expression, A program for executing a calculation execution step to be executed and an output step of outputting pharmacokinetic information that is information based on the execution result in the calculation execution step.

[7] In the biometric information receiving step!

 Receive biological information about biological information before starting simulation and during simulation,

 In the calculation execution step,

 The drug information received in the drug information reception step and the biological information received in the biological information reception step during the simulation are passed as parameters to the pharmacokinetic information output calculation formula, and the pharmacokinetic information output calculation formula is executed. The program according to claim 6 to be performed.

 [8] The pharmacokinetic information is

 8. The program according to claim 6 or claim 7, comprising at least site information indicating a site where the drug is absorbed and status information indicating the state of the drug.

[9] In the biometric information reception step!

 9. The program according to claim 6, which receives biological information that is a result of cell simulation simulating movement in a cell.