Predicting Hepatic Disposition Properties of Cationic Drugs Using a Physiologically Based, Agent-Oriented In Silico Liver

The In Silico Liver (ISL) plugs together autonomous soft-ware objects that represent hepatic components at different scales and levels of details. ISL parameters sensitive to drug-specific physicochemical properties (PCPs) were tuned so that ISL outflow profiles from a single ISL matched in situ perfused rat liver outflow profiles of sucrose and six cationic drugs. Antipyrine and diltiazem have the greatest degree of separation in PCP space of all pairs of the six compounds. Data for the other four, more closely spaced compounds comprised a training set for a simple artificial neural network (ANN) that was used to predict the PCP-sensitive, ISL parameter values for antipyrine and diltiazem given their PCPs. Those predicted parameter values were combined with the already-validated, drug-insensitive ISL parameter values. Simulation of the resulting ISLs gave ex-pected liver perfusion outflow profiles for antipyrine and diltiazem that were within two-fold of the observed profiles. 1