PT  - JOURNAL ARTICLE
AU  - Park, Sunwoo
AU  - Ropella, Glen E. P.
AU  - Kim, Sean H. J.
AU  - Roberts, Michael S.
AU  - Hunt, C. Anthony
TI  - Computational Strategies Unravel and Trace How Liver Disease Changes Hepatic Drug Disposition
AID  - 10.1124/jpet.108.142497
DP  - 2009 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 294--305
VI  - 328
IP  - 1
4099  - http://jpet.aspetjournals.org/content/328/1/294.short
4100  - http://jpet.aspetjournals.org/content/328/1/294.full
SO  - J Pharmacol Exp Ther2009 Jan 01; 328
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics