Effects of P450-selective inhibitors on the formation of 1′-and 4-hydroxymidazolam in wild-type and Tg-CYP3A4 mouse, and human intestinal microsomes
| Inhibitor | Concentration (μM) | P450 Isozyme | Relative Activity of Metabolite Formation | |||||
|---|---|---|---|---|---|---|---|---|
| 1′-OH-MDZ | 4-OH-MDZ | |||||||
| Wild-type | Tg-CYP3A4 | Human | Wild-type | Tg-CYP3A4 | Human | |||
| α-Naphthoflavone | 5 | 1A2 | 116 | 125 | 138 | 92 | 102 | 106 |
| Furafyllinc | 10 | 1A2 | 78 | 70 | 28 | 67 | 70 | 31 |
| 8-Methoxypsoralen | 10 | 1A2-2A6 | 60 | 81 | 21 | 56 | 86 | 23 |
| Orphenadrine | 200 | 2B6/2C/3A | 90 | 51 | 82 | 102 | 118 | 117 |
| Sulfaphenazole | 20 | 2C9 | 108 | 106 | 98 | 97 | 117 | 100 |
| S-Mephenytoin | 200 | 2C19 | 118 | 85 | 104 | 125 | 104 | 123 |
| Quinine | 5 | 2D6 | 96 | 112 | 106 | 93 | 124 | 108 |
| Quinine | 5 | 2D6 | 112 | 97 | 118 | 119 | 115 | 121 |
| Diethyldithiocarbamate | 100 | 2A6/2B6/2E1 | 59 | 33 | 16 | 73 | 77 | 25 |
| Ketoconazole | 2.5 | 3A4/5 | 5 | 1 | 4 | 9 | 3 | 9 |
| Troleandomycin | 10 | 3A4/5 | 7 | 6 | 4 | 13 | 10 | 7 |
Experiments were performed with a fixed midazolam concentration of 2.5 μM. Each value represents the mean of duplicate incubations.