Model-fitted Ki(app), Km, and Vmax parameters for inhibition of 3A4- and 3A5-Supersomes
Experiments were conducted in triplicate. Values reported are mean ± S.D. [of parameter estimate from competitive (C) inhibition model fit, except for ketoconazole, which was best fit by a noncompetitive (N) model]. A Ki(app) for the inhibition of CYP3A5 midazolam 4-hydroxylation by erythromycin and nicardipine could not be estimated.
Inhibitor | Model Type | 1¢-OH | Model Type | 4-OH | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ki(app) | Km | Vmax | Ki(app) | Km | Vmax | |||||||
| μM | μM | nmol/min/nmol | μM | μM | nmol/min/nmol | |||||||
| CYP3A4 + b5 | ||||||||||||
| Ketoconazole | N | 0.0278 ± 0.0005 | 4.1 ± 0.1 | 5.0 ± 0.1 | N | 0.0331 ± 0.0058 | 41.8 ± 15.6 | 9.6 ± 2.6 | ||||
| Erythromycin | C | 33.2 ± 2.7 | 4.3 ± 0.7 | 4.0 ± 0.3 | C | 110 ± 33 | 13.9 ± 3.2 | 2.7 ± 0.4 | ||||
| Diltiazem | C | 13.8 ± 1.6 | 2.5 ± 0.1 | 5.2 ± 0.1 | C | 40.0 ± 1.9 | 10.6 ± 1.9 | 2.8 ± 0.4 | ||||
| Nicardipine | C | 0.0085 ± 0.0011 | 3.9 ± 0.8 | 4.3 ± 0.3 | C | 0.0070 ± 0.0012 | 9.1 ± 2.2 | 1.7 ± 0.4 | ||||
| CYP3A5 + b5 | ||||||||||||
| Ketoconazole | N | 0.219 ± 0.006* | 4.7 ± 0.5 | 8.1 ± 0.3 | N | 0.148 ± 0.018* | 30.8 ± 4.6 | 2.8 ± 0.4 | ||||
| Erythromycin | C | 29.4 ± 4.9 | 4.0 ± 0.3 | 7.3 ± 0.1 | ||||||||
| Diltiazem | C | 42.6 ± 0.8* | 3.9 ± 0.2 | 9.8 ± 0.0 | C | 134 ± 10* | 21.2 ± 0.8 | 2.9 ± 0.1 | ||||
| Nicardipine | C | 0.091 ± 0.016* | 16.4 ± 4.4 | 10.3 ± 1.5 |
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↵* Significant difference between CYP3A5 and CYP3A4, p < 0.05.