Effects of ERAs on in vitro toxicity endpoints
Assessment of effects of ERAs on biliary transport (BSEP, MRP2), mitochondrial function (OCR, MRR), non-P450, and CYP3A4-mediated cell toxicity (THLE-NULL and THLE-Null/3A4 ratio). Values are means from independent replicate experiments, n ≥ 3. Compounds were classed as active if the IC50/EC50 values were ≤300 µM, BSEP and MRP2; ≤200 µM, OCR and MRR; ≤200 µM, THLE-Null; ≥1.4 THLE-Null/3A4 ratio.
| Drug | Parameter | Safety Assay Endpointa | Aggregate Safety Score | |||||
|---|---|---|---|---|---|---|---|---|
| BSEP IC50 | MRP2 IC50 | Basal OCR EC50 | MRR EC50 | THLE-Null EC50 | THLE Null/3A4 EC50 Ratio | |||
| Sitaxentan | Value | 10.4 | 61.0 | 135.5 | 60.6 | 160.0 | 1.8 | |
| Score | 1 | 1 | 0 | 1 | 1 | 1 | 5 | |
| Bosentan | Value | 28.0 | 215.1 | >250 | 211.2 | >300 | >1.5 | |
| Score | 1 | 1 | 0 | 0 | 0 | 1 | 3 | |
| Ambrisentan | Value | 288.1 | >1000 | >125 | >125 | >300 | nd | |
| Score | 1 | 0 | 0 | 0 | 0 | 0 | 1 | |
nd, not determined.
↵a All values except THLE Null/3A4 EC50 ratios are given in micromolar.