The drug-dependent parameters and characteristics of the presented PBPK model
| Parameter | R-Carvedilol | S-Carvedilol | Source/ Reference (R, S) |
|---|---|---|---|
| Molecular weight (g/mol) | 406.47 | 406.47 | PubChem. |
| LogPo:w | 4.19 | 4.19 | PubChem. |
| pKa | 7.97 | 7.97 | (Caron et al., 1999) |
| Absorption | |||
| Model | ADAM | ||
| Solubility (mg/mL)a | 0.01 | 0.01 | (Benet et al., 2011) |
| Peff,man (cm/s) | 3.9 × 10−4b | 1.6 × 10−4 | (Tian et al., 2012), Sensitivity analysis and manual optimization |
| fu,Gut | 0.00138 | 0.00124 | Simcyp predicted |
| QGut (L/h)c | 12.2 | 8.1 | Simcyp predicted |
| Distribution | |||
| Model | Full PBPK | ||
| Vss (L/kg)—predicted | 1.57 | 1.95 | Poulin and Theil method |
| Vss (L/kg)— observed | 1.39–3.40 | 1.42–3.84 | (Neugebauer et al., 1990) |
| Blood to plasma (B:P) ratio | 0.67 | 0.74 | (Fujimaki et al., 1990) |
| fuP | 0.0045 | 0.0063 | (Fujimaki et al., 1990) |
| Elimination | |||
| CLiv (L/h)—used as input in retrograde model | 41 | 54 | (Neugebauer et al., 1990), Optimized |
| CYP2D6 CLint (µL/min/mg/pmol isoform)d | 656.5 | 702.2 | Simcyp retrograde model of enzyme kineticsd,e |
| CYP1A2 CLint (µL/min/mg/pmol isoform)d | 2.7 | 21.6 | |
| CYP2C9 CLint (µL/min/mg/pmol isoform)d | 1.9 | 15.3 | |
| CYP3A4 CLint (µL/min/mg/pmol isoform)d | 0.5 | 4.1 | |
| CYP2E1 CLint (µL/min/mg/pmol isoform)d | 1.1 | 9.2 | |
| UGT1A1 CLint (µL/min/mg/pmol isoform)e | 8.8 | 9.1 | |
| UGT2B4 CLint (µL/min/mg/pmol isoform)e | 10.5 | 10.4 | |
| UGT2B7 CLint (µL/min/mg/pmol isoform)e | 8.9 | 19.6 | |
| CLR (L/h)f | 0.25 | 0.25 | (Gehr et al., 1999) |
ADAM, advanced, dissolution, absorption, and metabolism; CLint, intrinsic clearance; CLiv, i.v. clearance; CLR, renal clearance; fu,Gut, fraction unbound drug in enterocytes; fuP, fraction of unbound drug in plasma; LogPo:w, octonal-water partition coefficient; pKa, acid dissociation constant; QGut, hybrid term derived from villous blood flow and drug permeability through the enterocyte membrane.
↵a Assumed to be similar for both enantiomers.
b Human jejunum permeability calculated from Papp value of a Caco-2 assay by calibrating with atenolol and using Simcyp.
↵c Qgut value was adjusted according to decrease in hepatic blood flow in CHF patients; see Materials and Methods for details.
↵d Values calculated by using retrograde model in Simcyp.
↵e Values calculated manually by predicted additional clearance using retrograde model in Simcyp.
↵f Assumed to be similar in both enantiomers.