RT Journal Article
SR Electronic
T1 Computational Strategies Unravel and Trace How Liver Disease Changes Hepatic Drug Disposition
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 294
OP 305
DO 10.1124/jpet.108.142497
VO 328
IS 1
A1 Park, Sunwoo
A1 Ropella, Glen E. P.
A1 Kim, Sean H. J.
A1 Roberts, Michael S.
A1 Hunt, C. Anthony
YR 2009
UL http://jpet.aspetjournals.org/content/328/1/294.abstract
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