TABLE 1.
Inhibitory potency of INH for CYP450 isoformsa
| Substrate reaction probe | CYP450 isoform | Ki, μM (SD) | Mechanism of inhibition |
|---|---|---|---|
| S-Mephenytoin 4-hydroxylation | CYP2C19 | 13 (2.4) | Competitive |
| Omeprazole 5-hydroxylation | CYP2C19 | 25.4 (6.20) | Competitive |
| Omeprazole sulfone formation | CYP3A | 51.8 (2.5) | Noncompetitive |
| Midazolam 4-hydroxylation | CYP3A | 75.9 (7.8) | Noncompetitive |
| Chlorzoxazone 6-hydroxylation | CYP2E1 | 110 (33) | Noncompetitive |
| Dextromethorphan O-demethylation | CYP2D6 | 126 (23) | Competitive |
| Phenacetin O-deethylation | CYP1A2 | >1,000 | |
| Tolbutamide 4-methylhydroxylationb | CYP2C9 | 102 (17) | Noncompetitive |
| Flurbiprofen 4′-hydroxylation | CYP2C9 | >500 | Noncompetitive |
| Dextromethorphan N-demethylation | CYP3A | 474 (103) | Competitive |
a
To calculate the inhibition constants (Ki values) for each isoform, data obtained from three HLMs to construct Dixon plots were fitted to an appropriate nonlinear regression enzyme inhibition model. The mechanism of inhibition was decided graphically and from the enzyme inhibition models (see Materials and Methods).
b
In recombinant CYP2C9.