Effect of isoform-specific substrates and isoform-specific inhibitors on irbesartan oxidation
| Probe | CYP Investigated | Metabolic Constant | μM4-aConcentration | Inhibition |
|---|---|---|---|---|
| μM | -fold Kmor Ki | % | ||
| Substrates | Km | |||
| 7-Ethoxyresorufin | 1A1 | 0.2 | 2 (10-fold) | 5.8 |
| Phenacetin | 1A2 | 30 | 500 (17-fold) | 35.2 |
| Coumarin | 2A6 | 0.3 | 4 (13-fold) | 20.5 |
| Tolbutamide | 2C9 | 200 | 2500 (13-fold) | 75.9 |
| Mephenytoin | 2C19 | 10 | 500 (5-fold) | 5.2 |
| Dextromethorphan | 2D6 | 20 | 200 (10-fold) | 49.1 |
| Aniline | 2E1 | 15 | 500 (33-fold) | 4.8 |
| Nifedipine | 3A4 | 15 | 200 (13-fold) | 94.5 |
| Inhibitors | K i | |||
| α-Naphthoflavone | 1A1 | 0.01 | 0.1 (10-fold) | 0 |
| Furafylline | 1A2 | 3 | 30 (10-fold) | 0 |
| Pilocarpine | 2A6 | 4 | 30 (8-fold) | 65.6 |
| Sulfaphenazole | 2C9 | 0.3 | 1.5 (5-fold) | 35.4 |
| Quinidine | 2D6 | 0.4 | 3 (8-fold) | 0 |
| Diallyldisulfide | 2E1 | 100 | 500 (5-fold) | 36.5 |
| Ketoconazole | 3A4 | 0.015 | 0.3 (20-fold) | 5.0 |
Hepatic microsomes preparations (2 mg/ml) were incubated for 30 min with 50 μM irbesartan and 1 mM NADPH in the absence or the presence of specific CYP isoform probes (either substrates or inhibitors), and the sum of monohydroxyl irbesartan.
↵4-a At these investigated concentrations, the potency and selectivity on the isoform-selective substrate activity has been demonstrated, except for diallyldisulfide and pilocarpine (Bourrié et al., 1996).