Table 2. List of parameters varied in the human and rat SimPops and results of multiple regression analysis in human SimPops administered 600 mg/day troglitazone (TGZ) for 6 months.

Human and rat population samples incorporating variability in parameters governing bile acid homeostasis (Bile Acid SimPops) have been constructed previously.²⁰ Four parameters in the Drug PBPK Sub-model and two system-specific parameters also were varied. (See supplementary material for methods and data used for construction of SimPops). In the human SimPops administered 600 mg/day TGZ for 6 months, a multiple regression analysis was performed to identify the most important parameters in TGZ-mediated hepatotoxicity using 16 varied parameters as independent variables and minimum hepatic ATP as the dependent variable. Statistical significance and standardized coefficients were calculated using JMP 10.

Parameter Name	Parameter Description	Significance	Standardized Coefficienta
Bile Acid Homeostasis Sub-model
LCA-sulfate uptake Vmax	Maximum velocity of hepatic uptake of LCA-sulfate	N/S	−0.08
LCA-sulfate canalicular efflux Vmax	Maximum velocity of biliary excretion of LCA-sulfate	P< 0.001	0.41
CDCA-amide uptake Vmax	Maximum velocity of hepatic uptake of CDCA-amide	N/S	−0.01
CDCA-amide canalicular efflux Vmax	Maximum velocity of biliary excretion of CDCA-amide	P< 0.01	0.14
CDCA-amide basolateral efflux Vmax	Maximum velocity of hepatic basolateral efflux of CDCA-amide	N/S (P=0.06)	0.08
CDCA amidation Vmax	Maximum velocity of CDCA amidation in hepatocytes	N/S	0.06
LCA-amide sulfation Vmax	Maximum velocity of LCA-amide sulfation in hepatocytes	N/S	−0.06
LCA synthesis Vmax	Maximum velocity of LCA synthesis by the gut microbiome	P< 0.001	−0.21
Uptake regulation scaling factor	Scaling factor governing the magnitude of feedback regulation of hepatic uptake transporter function by hepatic bile acid accumulation	N/S	0.02
Canalicular efflux regulation scaling factor	Scaling factor governing the magnitude of FXR-mediated feedback regulation of hepatic canalicular transporter function by hepatic bile acid accumulation	P< 0.001	0.2
LCA hydroxylation Vmaxb	Maximum velocity of LCA hydroxylation in hepatocytes	N/A	N/A
Drug PBPK Sub-model
TGZ intestinal absorption Kab	First-order rate constant for TGZ absorption from intestine	N/S	−0.05
TGZ hepatic uptake Vmax	Maximum velocity of TGZ hepatic uptake	N/S	−0.07
TGZ sulfation Vmax	Formation rate of TGZ-sulfate (TS)	N/S	−0.06
TS biliary clearance	Biliary clearance of TS	P< 0.001	0.15
Other system-specific parameters
Body weightc	Body weight	P< 0.001	0.15
Toxicity Km for CDCA and LCA speciesc	Intracellular bile acid concentrations that induce half-maximal inhibition of ATP synthesis	P< 0.001	0.15

^aParameter estimates that would have resulted from the regression if all of the variables had been standardized to a mean of 0 and a variance of 1. The greater the absolute value of the standardized coefficient, the greater the effects of the independent variable on the model output.

^bUsed in rat SimPops only.

^cUsed in human SimPops only.

N/S, not significant.

N/A, not available.