Input parameters used for morphine physiologically based pharmacokinetic (PBPK) simulations
| PBPK Parameter | Control | Cirrhotic | Method/Reference |
|---|---|---|---|
| Molecular mass (g/mol) | 285.34 | Simcyp library | |
| LogP | 0.77 | Emoto et al. (2017) | |
| Acid dissociation constant (pKa) | 7.9 | Emoto et al. (2017) | |
| pKa2 | 9.6 | Emoto et al. (2017) | |
| Blood-to-plasma ratio | 1.08 | Emoto et al. (2017) | |
| Unbound fraction (Fu) | 0.62 | Emoto et al. (2017) | |
| Full PBPK model | |||
| Vss (liters/kg) | 3.6 | Method 2 (Rodgers et al., 2005) | |
| Enzyme kinetics | |||
| (HLM) | |||
| UGT2B7/M3G | |||
| Km (μmol/liter) of human liver microsomes (M3G) | 115.8 | Reported (Emoto et al., 2017) | |
| Vmax (pmol/min per milligram of microsomal protein) (M3G) | 9250 | 2035a | Reported (Emoto et al., 2017) |
| UGT2B7/M6G | |||
| Km (μmol/liter) HLM (M6G) | 115.8 | Emoto et al. (2017) | |
| Vmax (pmol/min per milligram microsomal protein) (M6G) | 1917 | 421.7a | Emoto et al. (2017) |
| Renal Cl (liters/h) | 8 | Emoto et al. (2017) | |
| Permeability limited liver model | |||
| Transporter kinetics | |||
| OCT1 (Km) μM | 3.4 | Emoto et al. (2017) | |
| OCT1 Jmax | 29 | 26.4a | Emoto et al. (2017) |
| OCT1 (REF) | 5.1 | Emoto 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.