Enabling clearance predictions to emerge from in silico actions of quasi-autonomous hepatocyte components.

We demonstrate the feasibility of using in silico hepatocyte cultures (ISHCs) to provide predictions of the intrinsic clearance (CL) of compounds in hepatocyte cultures. We compare results with predictions obtained using a multiple linear regression method. Our expectation is that the method can be extended to predict in vivo clearance of new compounds in humans.

Computational experiments reveal plausible mechanisms for changing patterns of hepatic zonation of xenobiotic clearance and hepatotoxicity.

No concrete, causal, mechanistic theory is available to explain how different hepatic zonation patterns of P450 isozyme levels and hepatotoxicity emerge following dosing with different compounds. We used the synthetic method of modeling and simulation to discover, explore, and experimentally challenge concrete mechanisms that show how and why biomimetic zonation patterns can emerge and change within agent-based analogues, expecting that those mechanisms may have counterparts in rats. Mobile objects map to compounds.

At the biological modeling and simulation frontier.

We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena.