The drug-dependent parameters and characteristics of the presented PBPK model

ParameterR-CarvedilolS-CarvedilolSource/ Reference (R, S)
Molecular weight (g/mol)406.47406.47PubChem.
pKa7.977.97(Caron et al., 1999)
Solubility (mg/mL)a0.010.01(Benet et al., 2011)
Peff,man (cm/s)3.9 × 10−4b1.6 × 10−4(Tian et al., 2012), Sensitivity analysis and manual optimization
fu,Gut0.001380.00124Simcyp predicted
QGut (L/h)c12.28.1Simcyp predicted
ModelFull PBPK
Vss (L/kg)—predicted1.571.95Poulin and Theil method
Vss (L/kg)— observed1.39–3.401.42–3.84(Neugebauer et al., 1990)
Blood to plasma (B:P) ratio0.670.74(Fujimaki et al., 1990)
fuP0.00450.0063(Fujimaki et al., 1990)
CLiv (L/h)—used as input in retrograde model4154(Neugebauer et al., 1990), Optimized
CYP2D6 CLint (µL/min/mg/pmol isoform)d656.5702.2Simcyp retrograde model of enzyme kineticsd,e
CYP1A2 CLint (µL/min/mg/pmol isoform)d2.721.6
CYP2C9 CLint (µL/min/mg/pmol isoform)d1.915.3
CYP3A4 CLint (µL/min/mg/pmol isoform)d0.54.1
CYP2E1 CLint (µL/min/mg/pmol isoform)d1.19.2
UGT1A1 CLint (µL/min/mg/pmol isoform)e8.89.1
UGT2B4 CLint (µL/min/mg/pmol isoform)e10.510.4
UGT2B7 CLint (µL/min/mg/pmol isoform)e8.919.6
CLR (L/h)f0.250.25(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.