Agent-Directed Tracing of Multi-Scale Drug Disposition Events within Normal and Diseased In Silico Livers

Abstract

Cirrhosis, a chronic liver disease, alters hepatic drug disposition; however, little is known about micro-mechanisms underpinning disease progression and how they contribute to changes in liver disposition properties. In this article, the authors present multilevel, agent-based and agent-directed In Silico Livers ISLs to probe plausible micro-mechanistic details for a cationic drug, diltiazem, in two different types of cirrhotic rat livers. Starting with ISLs that validated against diltiazem disposition data from normal livers, the authors systematically transformed ISL characteristics to achieve validation against perfusion outflow profiles from the two types of diseased livers. In this regard, the authors developed and implemented multilevel methods to trace each object representing diltiazem during simulated perfusion experiments. This enabled gaining heretofore-unavailable insight into plausible micro-mechanistic details from diltiazem's perspective in normal and diseased livers. The authors posit that the presented ISL micro-mechanistic details may have disease caused counterparts during disposition.