Table 6.
In Vitro ADME Profile of the Most Potent Inhibitor 8
| compound | |||||
|---|---|---|---|---|---|
| assay performed | in vitro ADMET | 8 | Ref1a | BMS-626529a | positive control used in the study (digoxin) |
| solubility (mg/mL) | phosphate buffer, pH7.4 | 0.734 | 0.042–0.214 | 0.047–0.237 | |
| Caco-2 permeability (mean Papp × 10−6 cm/sec) | A-to-B | 6.51 | 0.602 | 9.27 | 0.483 |
| B-to-A | 20.3 | 17.7 | 32.0 | 10.3 | |
| efflux ratio | 3.12 | 30.5 | 3.46 | 21.2 | |
| (+1 μM Valspodar) | A-to-B | 14.0 | 0.777b | 13.5b | 2.00 |
| B-to-A | 10.5 | 10.9b | 22.7b | 2.06 | |
| efflux ratio | 0.755 | 14.4b | 1.69b | 1.03 | |
| metabolic stability (human liver microsomes) | parent compound remaining at 120 min (% of 0 min) | 93.5 | 88.5 | 71.5 | |
| Clint (mL/min/mg protein) | <0.0116 | 0.0018 | 0.0052 | ||
| Half-life (min) | >120 | ||||
| protein binding (human plasma) | % bound | 99.2 | 99.0 | 86.9 | |
| cytochrome P450 inhibition, IC50 (μM) | CYP1A2 (Phenacetin) | 70.1 | >25 | >25 | |
| CYP2B6 (Bupropion) | 85.4 | >25 | >25 | ||
| CYP2C8 (Amodiaquine) | >100 | >25c | >25c | ||
| CYP2C9 (Diclofenac) | >100 | >25 | >25 | ||
| CYP2C19 (S-Mephenytoin) | >100 | >25 | >25 | ||
| CYP2D6 (Bufuralol) | >100 | >25 | >25 | ||
| CYP3A (Testosterone) | >62.2 | >25 | >25 | ||
| CYP3A (Midazolam) | >100 | >25 | >25 | ||
a
The data were from ref 10.
b
100 μM verapamil was used as a P-gp inhibitor
c
Paclitaxel was used as a substrate.