Table 1.
Summary of kinetic parameters for conversion of R- and S- methadone to R- and S-EDDP by CYP2B6, CYP2C19 and CYP3A4 and the hepatic CYP abundances, genotypes and corresponding phenotype frequencies
| CYP | R-methadone | S-methadone | Caucasian | Chinese | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Vmax, CYP (pmol/min/pmol CYP)a | Km, CYP (µM)a, b | ISEF (Caucasian/Chinese) | Catalytic efficiency (µl/min/mg protein) (Caucasian/Chinese) | Vmax, CYP (pmol/min/pmol CYP)a | Km, CYP (µM)a, b | ISEF (Caucasian/Chinese) | Catalytic efficiency (µl/min/mg protein) (Caucasian/Chinese) | Phenotype (frequency) | Mean abundance (μx, pmol/mg protein) | CV (%) | Phenotype (frequency) | Mean abundance (μx, pmol/mg protein) | CV (%) | |
| 2B6 | 36 | 60 | 0.13/0.072 | 1.16/0.22 | 15 | 16 | 0.13/0.049 | 1.81/0.24 | EM (0.89)c | 17c | 122c | EM (0.95)d | 5.3c | 198c |
| PM (0.11)c | 6c | 200c | PM (0.05)d | 1.9c | 200c | |||||||||
| 2C19 | 22 | 97 | 0.1/0.047 | 0.25/0.05 | 8 | 125 | 0.39/0.13 | 0.27/0.04 | General group | 11e | 82e | EM (0.87)c | 4.4c | 39c |
| 3A4 | 43 | 137 | 0.04/0.0062 | 1.21/0.23 | 46 | 149 | 0.03/0.0034 | 0.97/0.13 | General group | 93e | 81e | EM (1)d | 120f | 33f |
ISEF inter-system extrapolation factors, EM extensive metabolizer, PM poor metabolizer
aValues were obtained from the global analysis of racemate metabolism reported in Totah et al. (2007)
bThe reported dissociation constant (Ks) was used as Km assuming rapid equilibrium for formation of the enzyme methadone complex (dissociation of enzyme methadone complex rate constant, k2 > > the complex to the products conversion rate constant, k3)
cObtained from the Simcyp simulator V18 Release 1 (Certara)
dBased on Guan et al. (2006)
eValues were summarized by Achour et al. (2014) from different studies
fReported by Shu et al. (2000)