Pharmacokinetic parameters of midazolam and enzyme turnover used in the simulation
Parameter | Value | Source | Reference |
|---|---|---|---|
| Midazolam | |||
| Dose | 46,045 (nmol) | A, B, C | |
| 12,279 (nmol) | D | ||
| 9,669, 9,823 (nmol) | A, D | ||
| Fa | 1 | assumed | |
| Fg | 0.475 (-EM), 0.955 (+EM) | A | |
| 0.42 (-CAM), 0.83 (+CAM) | D | ||
| 0.42 (-AZM), 0.42 (+AZM) | |||
| fb | 0.033 | calculated from fu = 0.022, Rb = 0.66 | E, D |
| Kp | 1 | assumed | |
| Vliver | 2,800 (ml) | ||
| Vpv | 70 (ml) | ||
| Q | 1,610 (ml/min) | ||
| CLint | 15,000 (ml/min) | * | |
| CLint, 1 | 14,130 (ml/min) | α-hydroxylation, 84.8% of CLint (Table 3) | |
| CLint,2 | 870 (ml/min) | 4-hydroxylation, 15.2% of CLint (Table 3) | |
| Km, 1 | 3.8 (μM) | Table 3 | |
| Vmax, 1 | 53,700 (nmol/min) | calculated from Km, 1 × CLint, 1 | |
| Km,2 | 13.4 (μM) | Table 3 | |
| Vmax,2 | 11,700 (nmol/min) | calculated from Km,2 × CLint,2 | |
| ka | 0.02 (min-1) | * | |
| Vsys | 50,000 (ml) | * | |
| Enzyme | |||
| kdeg | 0.0005 (min-1) | rat P450 | F |
|
Eo
|
5 (nmol/g liver)
|
CYP3A4 content in the liver
|
G
|
EM, erythromycin; CAM, clarithromycin; AZM, azithromycin; fu, unbound fraction in plasma; Rb, blood to plasma concentration ratio.
A, Olkkola et al., 1993; B, Zimmermann et al., 1996; C, Yeates et al., 1996; D, Gorski et al., 1998; E, Lown et al., 1995; F, Shiraki and Guengerich, 1984; G, Iwatsubo et al., 1997.
↵* Calculated using eqs. 5 to 11 to fit the reported midazolam blood concentration (Olkkola et al., 1993).