Tracing multiscale mechanisms of drug disposition in normal and diseased livers

• Published in: The Journal of pharmacology and experimental therapeutics 2010-07, Vol.334 (1), p.124-136
• Main Authors: Park, Sunwoo, Kim, Sean H J, Ropella, Glen E P, Roberts, Michael S, Hunt, C Anthony
• Format: Article
• Language: English
• Subjects: Animals; Chemical and Drug Induced Liver Injury - metabolism; Diltiazem - pharmacokinetics; Disease Models, Animal; In Vitro Techniques; Liver - metabolism; Liver Diseases - metabolism; Liver Diseases, Alcoholic - metabolism; Male; Models, Biological; Monte Carlo Method; Pharmaceutical Preparations - metabolism; Rats; Rats, Wistar; Tissue Distribution
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.168526

Hepatic drug disposition is different in normal and diseased livers. Different disease types alter disposition differently. What are the responsible micromechanistic changes and how do they influence drug movement within the liver? We provide plausible, concrete answers for two compounds, diltiazem and sucrose, in normal livers and two different types of cirrhotic rat livers: chronic pretreatment of rats with carbon tetrachloride (CCl(4)) and alcohol caused different types of cirrhosis. We started with simulated disposition data from normal, multilevel, physiologically based, object-oriented, discrete event in silico livers (normal ISLs) that validated against diltiazem and sucrose disposition data from normal livers. We searched the parameter space of the mechanism and found three parameter vectors that enabled matching the three wet-lab data sets. They specified micromechanistic transformations that enabled converting the normal ISL into two different types of diseased ISLs. Disease caused lobular changes at three of six levels. The latter provided in silico disposition data that achieved a prespecified degree of validation against wet-lab data. The in silico transformations from normal to diseased ISLs stand as concrete theories for disease progression from the disposition perspective. We also developed and implemented methods to trace objects representing diltiazem and sucrose during disposition experiments. This allowed valuable insight into plausible disposition details in normal and diseased livers. We posit that changes in ISL micromechanistic details may have disease-causing counterparts.