Pharmacokinetic parameters estimated for midazolam and 1′-hydroxymidazolam in WT and Tg-CYP3A4 mice
| Parameters | Wild-Type | Tg-CYP3A4 | Tg-CYP3A4/WT | |||||
|---|---|---|---|---|---|---|---|---|
| Control | Ketoconazole | Ket/Cont | Control | Ketoconazole | Ket/Cont | Cont | Ket | |
| Midazolam | ||||||||
| T max(min) | 7.00 ± 4.00 | 12.5 ± 12.6 | 1.79 | 7.00 ± 2.90 | 12.0 ± 7.60 | 1.71 | 1.00 | 0.96 |
| C max(nmol/l) | 1,190 ± 957 | 1,360 ± 689 | 1.14 | 348 ± 93.7 | 1130 ± 180* | 3.25 | 0.29 | 0.83 |
| AUC0–180 min(nmol · min/l) | 13,200 ± 8040 | 43,100 ± 3310* | 3.27 | 8250 ± 429 | 52,300 ± 6750* | 6.34 | 0.62 | 1.21 |
| AUC0–∞(nmol · min/l) | 13,800 ± 8310 | 46,200 ± 5740* | 3.35 | 8330 ± 425 | 63,800 ± 11,500* | 7.66 | 0.60 | 0.90 |
| CLoral(l/min) | 0.90 ± 0.00 | 0.20 ± 0.00* | 0.22 | 0.93 ± 0.00 | 0.12 ± 0.00* | 0.13 | 1.03 | 0.60 |
| MRT (min) | 23.0 ± 15.3 | 39.7 ± 8.90* | 1.73 | 26.0 ± 2.70 | 41.7 ± 7.10* | 1.60 | 1.13 | 1.05 |
| t 1/2(min) | 34.3 ± 4.2 | 28.9 ± 11.9 | 0.84 | 18.7 ± 0.60 | 36.7 ± 4.70* | 1.96 | 0.55 | 1.27 |
| F-Bioavailability (%) | 21.5 ± 14.0 | ND | 10.1 ± 1.60 | ND | 0.47 | ND | ||
| 1′-OH-Midazolam | ||||||||
| T max(min) | 20.0 ± 0.00 | 30.0 ± 26.4 | 16.7 ± 5.8 | 46.7 ± 23.1* | 0.835 | 1.56 | ||
| C max(nmol/l) | 707 ± 199 | 901 ± 64 | 1.27 | 2290 ± 69 | 1121 ± 294* | 0.49 | 3.24 | 1.24 |
| AUC0–180 min(nmol · min/l) | 35,500 ± 8,560 | 64,700 ± 15,100 | 1.82 | 102,000 ± 6,800 | 85,500 ± 13,500 | 0.84 | 2.87 | 1.32 |
Values represent the mean ± S.D from three mice. Mice were orally administrated with midazolam (2.5 mg/kg). The effects of ketoconazole (Ket) were examined by predosing the mice with ketoconazole (45 mg/kg) at 45 min before the experiment. Control (Cont) mice did not have any treatment.
3-150 p < 0.05; ND, not determined; Ket, ketoconazole; cont, control.