Modeling and simulation of hepatic drug disposition using a physiologically based, multi-agent in silico liver.
OBJECTIVE
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.


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.
Yan
Li
L
The UCSF/UCB Joint Graduate Group in Bioengineering, University of California, Berkeley, CA 94720, USA.
Ropella
Glen E P
GE
Park
Sunwoo
S
Roberts
Michael S
MS
Hunt
C Anthony
CA
D002412:Cations / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D003201:Computers; D004347:Drug Interactions; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D011169:Portal Vein / Q000378:metabolism; D012984:Software; D013395:Sucrose / Q000494:pharmacology
D002412:Cations; D004364:Pharmaceutical Preparations; D013395:Sucrose