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Abstract The functional unit of IS-HIC is the hepatocyte, which is one component of the ISL and bears primary responsibility for metabolizing compounds found in the blood. The IS-HIC framework measures the extraction or clearance (CL) of compounds (in this case drugs) from the injected solution by the in silico hepatocytes. Where the ISL models hepatocytes in the context of their spatial and functional roles as a part of a lobule, the IS-HIC arranges the hepatocytes on a 2 dimensional grid as if they were in a petri dish. There is no blood flow and the hepatocytes simply sit in the solution and act upon compound molecules as they come into contact with them. In the ArtModel, hepatocytes are placed randomly in a 2D grid as fixed objects. Drug (and other) mobile objects are then randomly placed within the space (external to all hepatocytes) based on the initial concentrations of those compounds. The mobile objects move around pseudo-randomly, while the hepatocytes have the opportunity to “take up” and metabolize them. As the simulation progresses, the number of solute objects decreases as a consequence of metabolism. At intervals this number is counted, normalized and scaled to represent the concentration of the compound. Hepatocytes are very complex cells whose behavior can vary widely depending on their context. We began the IS-HIC partly to help develop these complex components separately from the ISL and partly as a mechanism to build a model of hepatocyte behavior in vitro. The aspect of this framework of methodological interest lies primarily in the fact that it is a simpler FURM construction and allows us to demonstrate elements and consequences of FURM that become more difficult with the more complex ISL. It also provides a test-bed for more advanced additions and developments to FURM like automatic selection and optimization of successful models and variations in SMs. However, the experimental framework of the IS-HIC is scientifically relevant to the study of hepatocytes and should help posit generative mechanisms at an even lower scale. |
