Input parameters used for morphine physiologically based pharmacokinetic (PBPK) simulations

PBPK ParameterControlCirrhoticMethod/Reference
Molecular mass (g/mol)285.34Simcyp library
LogP0.77Emoto et al. (2017)
Acid dissociation constant (pKa)7.9Emoto et al. (2017)
pKa29.6Emoto et al. (2017)
Blood-to-plasma ratio1.08Emoto et al. (2017)
Unbound fraction (Fu)0.62Emoto et al. (2017)
Full PBPK model
Vss (liters/kg)3.6Method 2 (Rodgers et al., 2005)
Enzyme kinetics
Km (μmol/liter) of human liver microsomes (M3G)115.8Reported (Emoto et al., 2017)
Vmax (pmol/min per milligram of microsomal protein) (M3G)92502035aReported (Emoto et al., 2017)
Km (μmol/liter) HLM (M6G)115.8Emoto et al. (2017)
Vmax (pmol/min per milligram microsomal protein) (M6G)1917421.7aEmoto et al. (2017)
Renal Cl (liters/h)8Emoto et al. (2017)
Permeability limited liver model
Transporter kinetics
OCT1 (Km) μM3.4Emoto et al. (2017)
OCT1 Jmax2926.4aEmoto et al. (2017)
OCT1 (REF)5.1Emoto et al. (2017)
  • M3G and M6G are morphine 3- and morphine-6 glucuronide; REF, relative expression factor.

  • a Jmax and Vmax values were respectively adjusted based on the change in OCT1 and UGT2B7 protein abundance in cirrhotic versus control liver reported previously by us (Wang et al., 2016) or here.