Circulator Is a New Technique for Systems Pharmacology
Metelkin E., Smirnov S., Gizzatkulov N., Demin O.
Institute for Systems Biology SPb, Moscow, Russia
Objectives: We have been developing the approach and software for modeling of complex biochemical system: metabolites and cells for whole organism. The main purpose of the project is the creating the tool for detailed description and simulation of following processes together:
- time dependent drugs and metabolites distribution in organism;
- blood circulation with exact geometry of vessels;
- blood cells migration and dynamics;
- signaling and metabolic processes in tissues, plasma and blood cells of each type;
- transport of metabolites and cytokines between plasma, blood cells and tissues;
- changes in blood cells states (maturation, viral infection and so on);
- complex mixing of blood from different organs.
Methods: Circulator describes the whole organism as the system of interconnected compartments which can exchange their liquid medium (blood). Each compartment can be described as the kinetic model that includes fixed phase (tissues) and movable phase (blood). The blood includes plasma and blood cells. Each cell type can be divided into several subtypes and groups describing the possible states of cells. Whole system is described as a system of ordinary differential equations with cell numbers and concentrations as variables.
Examples: On the basis of the software “Circulator 3” the models of following diseases and processes have been developed and analyzed:
- The template model of blood recirculation which includes 20 organs and 2199 compartments. The model can be expanded for the description of any drug and metabolites in organism.
- The model of diabetes I and II types and different treatment regimes;
- The PK/PD model of prostacyclin after bradykinin treatment which describes different pharmacokinetics depending on location of injection;
- Spatial distribution model of Ca2+ dynamics in trombocytes after local activation or inhibition;
- The model of lipid exchange in human.
Conclusion: Circulator approach can be used for modeling, simulation and prediction of processes of any complexity unavaliable for other approaches: PBPK, semi-mechanistic PK/PD modeling and so on.