Physiologic and kinetic parameters used for PBPK modeling
The kinetic parameters experimentally obtained from in vitro studies are presented as the mean ± S.D., unless otherwise indicated.
| Parameters | Value | Source |
|---|---|---|
| Physiologic parameters | ||
| Body weight (kg) | 78 | Weber et al. (1996) |
| Hepatocellular space (g/kg) | 6.69 | Davies and Morris (1993) |
| Extrachepatic space (g/kg) | 17.4 | |
| Adipose (g/kg) | 142 | |
| Muscle (g/kg) | 429 | |
| Skin (g/kg) | 111 | |
| Blood flow rate | ||
| Liver (ml/min per kilogram) | 20.7 | Davies and Morris (1993) |
| Adipose (ml/min per kilogram) | 3.72 | |
| Muscle (ml/min per kilogram) | 10.7 | |
| Skin (ml/min per kilogram) | 4.28 | |
| Tissue/blood concentration ratio | ||
| Adipose | 0.121 | Calculated from reported equations (Rodgers and Rowland, 2006) |
| Muscle | 0.119 | |
| Skin | 0.483 | |
| Kinetic parameters | ||
| Plasma unbound fraction | 0.02 | Weber et al. (1996), Dingemanse and van Giersbergen (2004) |
| Blood/plasma concentration ratio | 0.6 | |
| CLr (l/h) | 0.144 | |
| Vmax,uptake (pmol/min per 106 cells) | 47.4 ± 18.6 | Current study |
| Km,uptake (μM) | 1.33 ± 1.34 | |
| PSdif,inf (pmol/min per 106 cells) | 2.89 ± 0.46 | |
| Vmax,met,OH (pmol/min per milligram microsomal protein) | 16.4 ± 1.75 | |
| Km,met,OH (μM) | 6.40 ± 1.20 | |
| CLmet,OH,nonsaturable (μl/min per milligram microsomal protein) | 0.158 ± 0.015 | |
| Vmax,met,DES (pmol/min per milligram microsomal protein) | 7.53 ± 2.39 | |
| Km,met,DES (μM) | 4.80 ± 2.61 | |
| CLmet,DES,nonsaturable (μl/min per milligram microsomal protein) | 0.273 ± 0.025 | |
| fH | 0.0696 ± 0.0068 |
CL,met,DES,nonsaturable, nonsaturable CLmet for the production of desmethyl bosentan; CL,met_OH,nonsaturable, nonsaturable CLmet for the production of hydroxyl bosentan; Vmax,met,DES, Vmax,met for the production of desmethyl bosentan; Vmax,met,OH, Vmax,met for the production of hydroxyl bosentan.