TABLE 1.
Kinetic analyses of the metabolism of probe drugs by hepatic microsomes from HBN mice and wild-type controls
Assays were performed in triplicate for each concentration of substrate. S.D. values given are from the fit of the curve as calculated using the Michaelis-Menten equation (GraFit version 5 (Erithacus Software, Horley, UK)). For tolbutamide, the Hill equation (GraFit version 5) was used to fit the data, giving Hill coefficients (n) of 0.38 and 0.29 for wild type and HBN, respectively.
|
Substrate
|
Metabolite
|
Wild type
|
HBN
|
||
|---|---|---|---|---|---|
| Km | Vmax | Km | Vmax | ||
| μm | pmol/min/mg | μm | pmol/min/mg | ||
| Chlorzoxazone | 6-Hydroxychlorzoxazone | 47 ± 9 | 1930 ± 100 | 53 ± 6 | 387 ± 11 |
| Midazolam | 1′-Hydroxymidazolam | 2.1 ± 0.3 | 389 ± 15 | 2.0 ± 0.3 | 116 ± 4 |
| Midazolam | 4-Hydroxymidazolam | 13.3 ± 0.4 | 146 ± 2 | 7.7 ± 0.9 | 7.3 ± 0.3 |
| Phenacetin | Acetaminophen | 5.6 ± 1.0 | 133 ± 6 | 4.1 ± 0.7 | 77 ± 3 |
| Metoprolol | α-Hydroxymetoprolol | 84 ± 7 | 483 ± 14 | 99 ± 9 | 76 ± 3 |
| Metoprolol | O-Desmethylmetoprolol | 86 ± 9 | 1650 ± 2 | 157 ± 14 | 531 ± 21 |
| Tolbutamide | Hydroxytolbutamide | 11200 ± 3400 | 211 ± 17 | 165 ± 48 | 44 ± 165 |