Table 3

Predicted relative contributions (fi) of individual CYP isoforms to rates of amitriptyline N-demethylation and E-10 hydroxylation by human liver microsomes and SUPERMIX at substrate concentrations of 1.5 and 15 μM, using RAF estimates (Table 2) and kinetic parameters of amitriptyline biotransformation (Table 1) in eq.2

PathwayCYPHuman LiversSUPERMIX
fi at 1.5 μMfiat 15 μMfi at 1.5 μMfi at 15 μM
N-Demethylation1A20.148  ± 0.060.187  ± 0.080.1360.176
(0.059–0.235)(0.073–0.321)
2B60.03  ± 0.030.033  ± 0.0300
(0.003–0.083)(0.005–0.087)
2C80.186  ± 0.090.111  ± 0.050.2740.172
(0.059–0.275)(0.04–0.175)
2C90.153  ± 0.060.185  ± 0.070.2930.363
(0.097–0.301)(0.095–0.318)
2C190.41  ± 0.170.271  ± 0.130.1990.13
(0.128–0.642)(0.071–0.465)
2D60.055  ± 0.030.032  ± 0.020.0890.054
(0.029–0.108)(0.019–0.054)
3A40.017  ± 0.010.181  ± 0.110.0090.105
(0.005–0.04)(0.072–0.381)
E-10 hydroxylation2B60.044  ± 0.040.07  ± 0.0500
(0.006–0.115)(0.013–0.16)
2D60.641  ± 0.170.422  ± 0.170.8560.685
(0.354–0.878)(0.166–0.724)
3A40.315  ± 0.140.507  ± 0.140.1440.315
(0.117–0.569)(0.263–0.73)

Table entries are means ± S.D., with the range of values in parentheses. Data from CYP2C19 and 2D6 poor metabolizer livers were excluded in calculating means and range of values forN-demethylation; data from the CYP2D6 deficient liver was excluded for E-10 hydroxylation (n = 9 human livers forN-demethylation, n = 11 human livers for E-10 hydroxylation).