Physiological parameters of rat and pharmacokinetic parameters of midazolam and mibefradil used in the simulation
| Parameter | Value | Source | Reference |
|---|---|---|---|
| Physiological parameters of rat | |||
| Body weight | 250 g | Lin et al., 1982 | |
| Vh | 0.011 liter | Lin et al., 1982 | |
| Vpv | 0.00028 liter | Assumed | |
| Qh | 0.882 l/h | Lin et al., 1982 | |
| E0 | 5 nmol/g liver | CYP3A4 content in the liver in human | Iwatsubo et al., 1997 |
| kdeg | 0.03 h−1 | Rat P450 | Shiraki and Guengerich, 1984 |
| Midazolam | |||
| Dose | 2500 μg | Sekiguchi et al., 2008 | |
| Fa × Fg | 0.78 | Higashikawa et al., 1999; Kuze et al., 2009 | |
| fb, S | 0.049 | Poulin and Theil, 2002 | |
| Kp, S | 1 | Assumed | |
| CLint, S | 830 l/h | By fitting | |
| CLint, S, 1 | 740 l/h | Using contribution ratio of CYP3A2 | |
| CLint, S, 2 | 90 l/h | Using contribution ratio of CYP2C11 | |
| ka, S | 5.62 h−1 | By fitting | |
| Vsys, S | 0.949 liter | By fitting | |
| Mibefradil | |||
| Dose | 1500 μg | Sekiguchi et al., 2008 | |
| 3000 μg | Sekiguchi et al., 2008 | ||
| Fa × Fg | 1 | Assumed | |
| fb, I | 0.035 | Wiltshire et al., 1997a | |
| Kp, I | 1 | Assumed | |
| CLint, I | |||
| 6 mg/kg dosed | 75.6 l/h | By fitting | |
| 12 mg/kg dosed | 49.4 l/h | By fitting | |
| ka, I | |||
| 6 mg/kg dosed | 0.174 h−1 | By fitting | |
| 12 mg/kg dosed | 0.165 h−1 | By fitting | |
| Vsys, I | |||
| 6 mg/kg dosed | 3.81 liters | By fitting | |
| 12 mg/kg dosed | 3.55 liters | By fitting | |
| kinact, 1 | 23.1 h−1 | For 4-hydroxylation of MDZ by rrCYP3A2 | |
| kinact, 2 | 33.9 h−1 | For 1′-hydroxylation of MDZ by rrCYP2C11 | |
| KI, app, 1 | 130 μg/l | For 4-hydroxylation of MDZ by rrCYP3A2 | |
| KI, app, 2 | 5630 μg/l | For 1′-hydroxylation of MDZ by rrCYP2C11 |