Liver disease changes the disposition properties of drugs, complicating drug therapy management. We present normal and "diseased" versions of an abstract, agent-oriented In Silico Livers (ISLs), and validate their mechanisms against disposition data from perfused normal and diseased rat livers. Dynamic tracing features enabled spatiotemporal tracing of differences in dispositional events for diltiazem and sucrose across five levels, including interactions with representations of lobular microarchitectural features, cells, and intracellular factors that sequester and metabolize. Differences in attributes map to measures of histopathology. We measured disease-causing differences in local, intralobular ISL effects, obtaining until now unavailable views of how and where hepatic drug disposition may differ in normal and diseased rat livers from diltiazem's perspective. Exploration of disposition in less and more advanced stages of disease is feasible. The approach and technology represent an important step toward unraveling the complex changes from normal to disease states and their influences on drug disposition.Changes in drug disposition properties caused by liver disease complicate drug selection and therapy management. Recent advances in computational biology are providing new, broadly applicable strategies to unravel such complexities. How does cirrhosis (Hung et al., 2002a,b) cause observed changes in hepatic drug disposition? More detailed understanding of precisely how drugs behave in diseased relative to normal livers requires new modeling strategies in which events at different levels can be observed and measured in both space and time. We address this need and provide a novel means of creating and testing real, working representations of hypothesized mechanisms. We present and validate a plausible explanation for structural and functional differences in the normal and diseased rat livers from the perspective of a specific drug, diltiazem (Hung et al., 2001), a cationic compound known to interact with hepatic components at all levels. We then show how those changes may have caused the observed differences in diltiazem's disposition.The In Silico Liver (ISL) Yan et al., 2008a,c) in Fig. 1 is an abstract analog built in software using discrete, object-oriented methods. It is an advanced example of what has been referred to as executable biology (Fisher and Henzinger, 2007;Hunt et al., 2008). ISLs are physiologically based, multilevel analogs of livers undergoing perfusion. They are not intended to be accurate, precise descriptions of how we think the liver works nor are they intended to provide precise, accurate predictions. Rather, they help us reduce uncertainties about hepatic mechanisms enabling us to refine, explore, and test hypotheses about the mechanistic details of hepatic drug disposition. In depicting three-dimensional hepatic morphology at a cellular level, it uses quasiautonomous components that recognize and interact uniquely with mobile objects representing different compounds. The...