Table 1.
Inhibition of CYP isoforms by ticlopidine. Data obtained from three HLMs to construct Dixon plots were fitted to an appropriate nonlinear regression enzyme inhibition model to calculate the inhibition constants (Ki values) for each isoform. The mechanism of inhibition was decided graphically and from the enzyme inhibition models (see Methods section).
| Substrate reaction probes | CYP450 isoforms | Ki (s.d. µm) | Mechanism of inhibition |
|---|---|---|---|
| (S)-Mephenytoin 4-hydroxylation | CYP2C19 | 1.2 (0.5) | Competitive* |
| Dextromethorphan O-demethylation | CYP2D6 | 3.4 (0.3) | Competitive |
| Phenacetin O-deethylation | CYP1A2 | 49 (19) | Competitive |
| Tolbutamide 4-methylhydroxylation | CYP2C9 | 76 (11) | Competitive |
| Flurbiprofen 4′-hydroxylation | CYP2C9 | 89 (12) | Noncompetitive |
| Chlorzoxazone 6-hydroxylation | CYP2E1 | 584 (148) | Competitive |
| Midazolam 4-hydroxylation | CYP3A | none** | |
| Dextromethorphan N-demethylation | CYP3A | none** |
*
Data equally fitted to competitive and noncompetitive model
**
estimated Ki > 1 mm.