Evaluating an Hepatic Enzyme Induction Mechanism Through Coarse- and Fine-grained Measurements of an In Silico Liver

Glen E. P. Ropella[1], Sunwoo Park[1], and C. Anthony Hunt[1,2]
gepr@tempusdictum.com, parks@pharmacy.ucsf.edu, a.hunt@ucsf.edu

[1] Joint UCSF/UCB Bioengineering Graduate Group and The Department of Biopharmaceutical Sciences, The Biosystems Group, The University of California, San Francisco, CA 94143, USA

[2] Joint UCSF/UCB Bioengineering Graduate Group, The University of California, San Francisco, CA 94143, USA

We present the results from enzyme induction experiments performed on a synthetic, physiologically based, multi-agent, In Silico Liver (see DOI: 10.1007/s10928-006-9031-3), which has been validated against in situ extraction profile data. These experiments, as formulated, are not feasible on actual livers and are intended to help formulate new experiments on the synthetic model and its referent. The experimental results falsify the hypothesis that a uniform distribution of simulated drug will produce a uniform distribution of enzyme induction activity within the artificial lobule structure. The results indicate a further, more refined experimental program for the model. We also discuss methodological considerations that arise in the execution of experiments using multi-level observation and manipulation of synthetic models and their referents.