Modelling and simulation of hepatic drug disposition using physiologically based, multi-agent in silico liver

Yan, Li, Ropella, Glen E. P., Park, Sunwoo, Roberts, Michael S. and Hunt, C. Anthony (2008) Modelling and simulation of hepatic drug disposition using physiologically based, multi-agent in silico liver. Pharmaceutical Research, 25 5: 1023-1036. doi:10.1007/s11095-007-9494-y

Author Yan, Li
Ropella, Glen E. P.
Park, Sunwoo
Roberts, Michael S.
Hunt, C. Anthony
Title Modelling and simulation of hepatic drug disposition using physiologically based, multi-agent in silico liver
Journal name Pharmaceutical Research   Check publisher's open access policy
ISSN 0742-8741
Publication date 2008-05
Sub-type Article (original research)
DOI 10.1007/s11095-007-9494-y
Volume 25
Issue 5
Start page 1023
End page 1036
Total pages 14
Editor V. H. L. Lee
Place of publication United States
Publisher Springer New York LLC
Collection year 2009
Language eng
Subject C1
970111 Expanding Knowledge in the Medical and Health Sciences
111501 Basic Pharmacology
Formatted abstract
Purpose Validate a physiologically based, mechanistic, in silico liver (ISL) for studying the hepatic disposition and metabolism of antipyrine, atenolol, labetalol, diltiazem, and sucrose administered alone or in combination.
Materials and Methods Autonomous software objects representing hepatic components such as metabolic enzymes, cells, and microarchitectural details were plugged together to form a functioning liver analogue. Microarchitecture features were represented separately from drug metabolizing functions. Each ISL component interacts uniquely with mobile objects. Outflow profiles were recorded and compared to wet-lab data. A single ISL structure was selected, parameterized, and held constant for all compounds. Parameters sensitive to drug-specific physicochemical properties were tuned so that ISL outflow profiles matched in situ outflow profiles.
Results ISL simulations were validated separately and together against in situ data and prior physiologically based pharmacokinetic (PBPK) predictions. The consequences of ISL parameter changes on outflow profiles were explored. Selected changes altered outflow profiles in ways consistent with knowledge of hepatic anatomy and physiology and drug physicochemical properties.
Conclusions A synthetic, agent-oriented in silico liver has been developed and successfully validated, enabling us to posit that static and dynamic ISL mechanistic details, although abstract, map realistically to hepatic mechanistic details in PBPK simulations.
Electronic supplementary material The online version of this article (doi:10.1007/s11095-007-9494-y) contains supplementary material, which is available to authorized users.
Keyword agent-based
complex systems
discrete event
physiologically based
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 23 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 31 Mar 2009, 21:44:04 EST by Maree Knight on behalf of Faculty Of Health Sciences