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

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).