Table 1.
Toxicity Parameters for Human and Rat
| Human | Rat | |
|---|---|---|
| Bile acid transporter inhibition constant (µM) | ||
| BSEP | 94a | 129.7b |
| MRP3 | 11.2 | 11.2c |
| MRP4 | 12.3 | 12.3c |
| NTCP | 19.5 | 19.5c |
| Mitochondrial toxicity constant (mM) | ||
| ETC inhibition constant | 14.2 | 1.42 |
| ROS production constant (mL/mol/h) | ||
| ROS production constant | 7278 | 9705 |
Transporter inhibition constants for CKA pertaining to bile acid and bilirubin were used as Ki values in simulating CKA-mediated hepatotoxicity. The electron transport chain (ETC) inhibition constant and reactive oxygen species (ROS) production constant parameters were optimized to data using MITOsym and DILIsym, respectively. IC50 values, non-competitive inhibition assumed for efflux transporters (BSEP, MRP3, MRP4), competitive inhibition assumed for uptake transporter (NTCP). For transporters where data were lacking, the same IC50 value was assumed across species, as indicated.
a
Data from Astra Zeneca (unpublished).
b
From Ulloa et al (2013).
c
Assumed to be the same as human.