Falsifying an Enzyme Induction Mechanism within a Validated, Multiscale Liver Model

Falsifying an Enzyme Induction Mechanism within a Validated, Multiscale Liver Model

Glen E. P. Ropella (Tempus Dictum, Inc., USA), Ryan C. Kennedy (University of California, USA) and C. Anthony Hunt (University of California, USA)
Copyright: © 2012 |Pages: 14
DOI: 10.4018/jats.2012070101
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Abstract

The focus is an In Silico Liver (ISL) model family and an evolving suite of mechanistic hypotheses about (rat) liver-drug interactions. ISLs are multiscale and hierarchical. A medium grain Enzyme Induction mechanism was implemented. Validation (falsification) of complicated, knowledge-based models requires integrating distinct aspects and methods for multi-aspect validation. For ISLs, such integration has not been straightforward. Falsification is crucial for formulating, testing, and iteratively evolving hypotheses about liver mechanisms. During multi-aspect falsification, the authors can falsify a hypothesis in one aspect while simultaneously validating it in another aspect. The authors demonstrate a multi-scalar validation/falsification event in which they validate the mechanism against coarse grain measures of liver perfusate drug levels and falsify it against a medium grained measure of hepatic zonation. The authors also discuss how falsification is guiding mechanism (hypothesis) refinement. The ability to scale validation efforts is necessary for effective scientific use models such as ISLs.
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Use Case

The target of this study is hepatocytes' ability to regulate (up or down) their enzymes in response to encountered compounds and other physiological signals (Hung, Chang, Cheung, McWhinney, Masci, Weiss & Roberts, 2005; Hunt, Ropella, Lam, Tang, Kim, Engelberg, & Sheikh-Bahaei, 2009; Hunt, Ropella, Yan, Hung, & Roberts, 2006). The use case is the experimental protocol for a single-pass, in situ, isolated perfused rat liver. The liver is first perfused with an oxygenated fluid. A bolus of compound is then added to the perfusate and a fraction collector protocol is next used to measure perfusate contents as it flows out of the liver. This use case exercises many of the steady state and fast transient aspects of hepatic function and was used to study the in situ clearance of cationic drugs (Kim, Park, Ropella, & Hunt, 2010). That study’s results provide the coarse-grained validation aspect on which we focus: the fraction of compound exiting in relation to the amount of compound in the bolus. Validation of various ISLs against data from the cited experiments is presented in several previous reports (Lam & Hunt, 2010; Lerapetritou, Georgopoulos, Roth, & Androulakis, 2009; Mankowski & Ekins, 2003; Oinonen, & Lindros, 1998; Park, Ropella, Kim, Roberts, & Hunt, 2009; Park, Kim, Ropella, Kim, Roberts, & Hunt, 2010).

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