Table 1.
Summary of physicochemical parameters, in vitro and in vivo data of morphine from the literature
| Parameter | Value |
|---|---|
| Molecular weight (g/mol) | 285.3414 |
| Log P | 0.7714 |
| pKa (proton on N) | 7.9315 |
| pKa (phenolic H) | 9.6315 |
| Fraction unbound in plasma | 0.6214 |
| Blood‐to‐plasma ratio | 1.0816 |
| Plasma binding protein | Human serum albumin (assumed) |
| Full PBPK model | |
| Vss (Rodgers and Rowland,19 L/kg) | 3.6 |
| Apparent Vd after i.v. administration (L/kg) | 4.017 |
| Elimination | |
| Enzyme kinetics (HLM) a | |
| UGT2B7/3MG | |
| Km (µM) | 115.814 |
| Vmax (pmol/min/mg microsomal protein) | 9,25014 |
| UGT2B7/6MG | |
| Km (µM) | 115.814 |
| Vmax (pmol/min/mg microsomal protein) | 1,91714 |
| Total CL (L/hr) | 84 b |
| Urine excretion ratio (%) | 10 c |
| Renal CL estimate (L/hr) | 8 |
| Permeability limited liver model (PerL) | |
| Transporter kinetics (HEK293 transfected cells) | |
| OCT1 Km (µM) | 3.4 ± 0.3 (mean ± SEM)6 |
| OCT1*1 (Wild) Jmax (pmol/min/mg lysate protein) | 29.0 ± 2.76 |
| OCT1*2 (420del) Jmax (pmol/min/mg lysate protein) | 7.21 ± 0.76 |
| OCT1*3 (61Cys) Jmax (pmol/min/mg lysate protein) | 6.25 ± 0.96 |
CL, clearance; HEK293, human embryonic kidney 293; HLM, human liver microsome; Km, kinetic metabolite; OCT1, organic cation transporter‐1; PBPK, physiologically based pharmacokinetic; UGT, uridine 5′‐diphosphate glucuronosyltransferase; Vmax, maximum velocity; Vss, volume of distribution at steady state.
aAssumed fu,mic= 1. bTotal CL was recalculated using AUC (ng/mL*hr) after i.v. administration and morphine free base dose (mg).18 cUrinary excreted ratio of unchanged morphine was assumed to be 10% from the data of package insert (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202515s000lbl.pdf) and the report by Osborne et al.4 and Hasselstrom and Sawa.5