TABLE 1.
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.
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.
No value was obtained since the rates at the highest concentration of oprozomib evaluated (30 µM) were higher than the control rates.