QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.108.142497v1 328/1/294    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Park, S. Articles by Hunt, C. A. Search for Related Content PubMed PubMed Citation Articles by Park, S. Articles by Hunt, C. A.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Computational Strategies Unravel and Trace How Liver Disease Changes Hepatic Drug Disposition

The Department of Bioengineering and Therapeutic Sciences, BioSystems Group, University of California, San Francisco, California (S.P., G.E.P.R., C.A.H.); the University of California San Francisco/University of California Berkeley Joint Graduate Group in Bioengineering, University of California, San Francisco, California (S.H.J.K., C.A.H.); and School of Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland, Australia (M.S.R.)

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.

Address correspondence to: C. Anthony Hunt, Department of Bioengineering and Therapeutic Sciences, University of California, 513 Parnassus Ave., S-926, San Francisco, CA 94143-0446. E-mail: a.hunt{at}ucsf.edu