Fig 1.
Discovering plausible mechanism-based explanations contributing to IVIVE discrepancies.
(A) Starting with a failed IVIVE prediction of hepatic clearance, the plan requires vCulture and vHuman analogs that have achieved multiple validation targets. Stage One establishes a direct quantitative mapping between measures of removal of vCompound during vCulture experiments and the data used to compute intrinsic clearance. Independently, Stage Two establishes a direct quantitative mapping between vCompound removal measures during vHuman experiments and the data used to compute hepatic clearance. We then explain vCompound disposition and removal differences and use that information to posit explanations for the observed IVIVE discrepancy. (B) The blue and yellow circles illustrate comparable per vHPC measures of disposition and removal for different vCompound properties. Measures from each system are quantitatively equivalent within the area of overlap. The black circle illustrates a vCompound that achieves the cross-system validation target (see text), whereas the two grey circles illustrate one that does not.
Fig 2.
(A) A vHuman comprises a well-mixed Body space, a vLiver, and a space for Dose. (B) A portion of vLiver. Graph edges designate flow connections within and between Layers. (C) A multi-layered, quasi-3D Sinusoidal Segment maps to a portion of lobular tissue. It comprises a Core surrounded concentrically by the four 2D grids described in the text. Mobile vCompound objects move within and between these grids. (D) A Sinusoidal Segment contains two Cell types. Each type controls vCompound entry from and exit to an adjacent space. The Cell and the components within determine the fate of vCompounds that enter. We list specification details in S1 Table.
Fig 3.
vCulture configuration and relative PV-to-CV vHPC density within vLobules.
(A) A vCulture comprises a Media Space plus a single Layer of same-size SS objects (reduced relative to those in Fig 2C). The well-mixed Media Space functions the same as Body. Specification details are listed in S1 Table. (B) Each bar’s height represents the mean number of vHPCs at the indicated vLobule location averaged over 12 Monte Carlo executions. Moving left-to-right from PV (dPV), the first 15 bars correspond to locations at increasing distances from PV along the average PV-to-CV path. Moving right-to-left, the first 10 bars correspond to locations at increasing distances from CV along the average CV-to-PV path. We average measures within the Periportal, Centrilobular, and Pericentral bands to characterize PV-to-CV differences in vCompound Entry and removal rates per vHPC.
Fig 4.
Results from vCulture experiments using vC1.
Changing pEnter alters vCompound dynamics during each experiment. Temporal values here, and in the subsequent figures, are centered moving averages spanning 181 TS. (A) Temporal measures of percent Dose in Media for each pEnter; blue measures are for Marker. (B) Temporal measures of mean Entry rates. (C) Mean dynamic steady-state Entry rates for each pEnter. (D) Temporal measures of percent Dose and (E) mean dynamic steady-state values of percent Dose within all vHPCs for each pEnter.
Fig 5.
Results from vHuman experiments using vC1.
(A) Temporal measures of percent Dose in Body for each pEnter. (B) Temporal measures of mean Entry rates for each pEnter. (C) Correlation between mean dynamic steady-state Entry rates and pEnter. (D) Temporal measures of percent Dose in vHPCs for each pEnter. (E) Correlation between mean dynamic steady-state amounts of vC1 in vHPCs and pEnter. Measures in F-H are mean dynamic steady-state values within the Periportal, Centrilobular, and Pericentral bands in Fig 3B. (F) Correlation between mean dynamic steady-state Entry rates and pEnter. (G) Correlation between vC1 amounts per vHPC and (H) total amounts within all vHPC and pEnter.
Fig 6.
Results from vCulture experiments using vC2.
(A) Temporal measures of percent Dose in Media for each pEnter. Blue profile: added all vC2 to Media at t = 0. (B) Mean removal rates for each pEnter (Entry rates = removal rates). (C) Correlation between mean peak Entry rates and pEnter. (D) Temporal measures of Extraction Ratio for each pEnter. Average variance increases with time because smaller amounts are measured each TS. Extraction Ratios for pEnter = 1.0 and 0.8 terminate because (essentially) all vC2 has been removed. (E) Correlation between mean plateau Extraction Ratios and pEnter. (F) Temporal measures of cumulative percent Dose in vHPCs for each pEnter. Insert: mean values at t = 3,000 TS for each pEnter.
Fig 7.
Results from vHuman experiments using vC2.
(A) Temporal measures of percent Dose in Body for each pEnter. Blue profile: all vC2 was added to Media at t = 0. (B) Mean Entry rates for each pEnter (Entry rates = removal rates). (C) Correlation between mean peak Entry rates and pEnter. To facilitate comparisons, the blue curve traces the corresponding values from Fig 6C. (D) Temporal measures of Extraction Ratio for each pEnter. For p ≥ 0.2, measures terminate early because (essentially) all vC2 has been removed. Variance increases with time because smaller amounts are measured. (E) Correlation between mean plateau Extraction Ratios and pEnter. (F) Temporal measures of cumulative percent Dose in vLiver for each pEnter. Note that, compared to Fig 6F, vLiver removal of vC2 is strikingly more efficient. (G) Peak Entry rates for each pEnter within the three bands in Fig 3A. Corresponding measures of percent Dose (H) and percent Dose per vHPC (I) at 7500 TS.
Fig 8.
Results from vCulture and vHuman experiments using vC3.
(A) Temporal measures of percent Dose in Body (top) and Media (bottom) for each pEnter. (B) Amount of Metabolite in Body (top) and Media (bottom) as percent of Dose for each pEnter. (C) Correlations between mean peak Entry rates and pEnter. (D) Correlations between mean Extraction Ratios and pEnter.
Fig 9.
Results from vCulture and vHuman experiments using vC4.
(A) Temporal measures of percent Dose in Body (top) and Media (bottom) for each pEnter. (B) Amount of Metabolite in Body (top) and Media (bottom) as percent of Dose for each pEnter. (C) Correlations between mean peak Entry rates and pEnter. (D) Correlations between mean plateau values of Extraction Ratio and pEnter. (E) Correlations between systemwide mean peak amounts of vC4 (objects) per vHPCs and pEnter. (F) Correlations between mean peak amounts of vC4 per vHPCs within the three vLiver bands and pEnter. (G) Correlations between mean peak Entry rates within the three bands and pEnter.