Effect of zileuton racemate on various P450 activities in human liver microsomes in the absence of preincubation
Duplicate IC50 values were obtained using human liver microsomes. In each case, the inhibition was compared with a solvent-alone control. IC50 values were obtained at a single concentration of substrate (paclitaxel, 15 μM; phenacetin, 100 μM; diclofenac, 10 μM; (S)-mephenytoin, 80 μM; bufuralol, 15 μM; testosterone, 50 μM; chlorzoxazone, 200 μM; and bupropion, 100 μM) as described under Materials and Methods. The percentage inhibition observed at the highest concentration of zileuton tested (100 μM) was <5% (CYP2D6 and CYP2C8), ∼15% (CYP1A2, CYP2E1, and CYP2C9), 40% (CYP2B6 and CYP3A4), and 45% (CYP2C19).
P450 Form | Reaction | Test Article | IC50 | ||
|---|---|---|---|---|---|
| 1 | 2 | ||||
| μM | |||||
| CYP1A2 | Phenacetin O-deethylation | Fluvoxamine | 0.4 | 0.4 | |
| Zileuton | >100 | >100 | |||
| CYP2C8 | Paclitaxel 6α-hydroxylation | Quercetin | 3.5 | 4.8 | |
| Zileuton | >100 | >100 | |||
| CYP2C9 | Diclofenac 4′-hydroxylation | Sulfaphenazole | 0.5 | 0.5 | |
| Zileuton | >100 | >100 | |||
| CYP2C19 | (S)-Mephenytoin 4′-hydroxylation | (R)-N-3-Benzylphenobarbital | 0.3 | 0.3 | |
| Zileuton | >100 | >100 | |||
| CYP2D6 | Bufuralol 1′-hydroxylation | Quinidine | 0.1 | 0.1 | |
| Zileuton | >100 | >100 | |||
| CYP3A4 | Testosterone 6β-hydroxylation | Ketoconazole | 0.02 | 0.05 | |
| Zileuton | >100 | >100 | |||
| CYP2B6 | Bupropion hydroxylation | N-(α-Methylbenzyl)-1-aminobenzotriazole | 0.03 | 0.05 | |
| Zileuton | >100 | >100 | |||
| CYP2E1 | Chlorzoxazone 6-hydroxylation | 4-Methylpyrazole | 3.0 | 1.79 | |
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| Zileuton | >100 | >100 | |