In vitro evaluation of boceprevir (BOC) as an inhibitor of major cytochrome P450 (P450) and UGT enzymes in human liver microsomes
| Enzyme | CYP/UGT Reaction | Substrate Concentration | Reversible Inhibition, No Preincubation | Time-Dependent Inhibition, 30-Minute Preincubationa | ||
|---|---|---|---|---|---|---|
| IC50 (Ki) | Inhibition (%) at 100 µM | IC50 | Inhibition (%) at 100 µM | |||
| µM | µM | µM | ||||
| CYP1A2 | Phenacetin O-deethylation | 60 | >100 | 22 | >100 | 9.8 |
| CYP2A6 | Coumarin 7-hydroxylation | 0.75 | >100 | 20 | >100 | 7.8 |
| CYP2B6 | Bupropion hydroxylation | 50 | >100 | 2.3 | >100 | 6.9 |
| CYP2C8 | Amodiaquine N-dealkylation | 2.0 | >100 | 25 | >100 | NA |
| CYP2C9 | Diclofenac 4′-hydroxylation | 7.5 | >100 | 3.6 | >100 | NA |
| CYP2C19 | S-Mephenytoin 4′-hydroxylation | 40 | >100 | 25 | >100 | 14 |
| CYP2D6 | Dextromethorphan O-demethylation | 7.5 | >100 | 45 | >100 | 30 |
| CYP2E1 | Chlorzoxazone 6-hydroxylation | 30 | >100 | NA | >100 | NA |
| CYP3A4/5 | Testosterone 6β-hydroxylation | 100 | >100 | 41 | 2.3 ± 0.2 | 95 |
| CYP3A4/5 | Midazolam 1′-hydroxylation | 5.0 | 11 ± 1.0 (7.7 ± 0.8) | 91 | 1.0 ± 0.1 | 99 |
| UGT1A1 | Estradiol 3-glucuronidation | 20 | >100 | 40 | ND | ND |
| UGT2B7 | 3′-azido-3′-deoxythimidine (AZT) glucuronidation | 750 | >100 | 10 | ND | ND |
NA, not applicable (no value was obtained as the rates at the highest concentration of BOC evaluated [100 µM] were higher than the control rates); ND, not determined.
↵a Time-dependent inhibition was determined by comparison of IC50 values with and without preincubation.