TABLE 1.
In vitro evaluation of oprozomib as an inhibitor of six human P450 enzymes
Results representing the average data (i.e., percentage of control activity) obtained from duplicate samples from each test article concentration were used to calculate the IC50 values. The IC50 values were calculated using GraphPad Prism (version 6). The highest concentration of oprozomib tested in the assays was 30 µM.
| Enzyme |
P450 Reaction |
Inhibition of Human P450s by Oprozomib | |||
|---|---|---|---|---|---|
| Direct (0-Minute Preincubation) |
Time Dependent (30-Minute Preincubation) |
||||
| IC50 |
Inhibition at 30 µMa |
IC50 |
Inhibition at 30 µMa |
||
| µM | % | µM | % | ||
| CYP1A2 | Phenacetin O-deethylation | >30 | 21 | >30 | NAb |
| CYP2C8 | Amodiaquine N-dealkylation | >30 | 20 | >30 | 13 |
| CYP2C9 | Diclofenac 4′-hydroxylation | >30 | 6.3 | >30 | 24 |
| CYP2C19 | S-Mephenytoin 4′-hydroxylation | >30 | 16 | >30 | 7.2 |
| CYP2D6 | Dextromethorphan O-demethylation | >30 | 0.2 | >30 | 3.7 |
| CYP3A4/5 | Testosterone 6β-hydroxylation | >30 | 45 | 5.5 | 89 |
| CYP3A4/5 | Midazolam 1′-hydroxylation | >30 | 33 | 12 | 68 |
NA, not applicable.
a
The inhibition (%) was calculated using the data for the highest concentration of test article evaluated and the following formula: inhibition (%) = 100% − % activity remaining of solvent control.
b
No value was obtained since the rates at the highest concentration of oprozomib evaluated (30 µM) were higher than the control rates.