Unbiased kinetic parameters of amitriptyline biotransformation by lymphoblast-expressed human CYP isoforms
Pathway | CYP | Km1-a | S501-a | Vmax1-b | A | Ks1-a | Clint1-c |
---|---|---|---|---|---|---|---|
N-Demethylation | 1A21-d | 63.5 ± 18.9 | 1.79 ± 0.23 | 28.2 | |||
2B6 | 56.7 ± 8.8 | 0.25 ± 0.01 | 4.4 | ||||
2C8 | 9.74 ± 3.4 | 0.7 ± 0.13 | 70 ± 24.4 | 71.9 | |||
2C91-d | 50.5 ± 10.2 | 3.97 ± 0.32 | 78.6 | ||||
2C19 | 8.52 ± 1.3 | 4.22 ± 0.2 | 639 ± 131 | 495.3 | |||
2D6 | 7.12 ± 0.6 | 1.49 ± 0.03 | 1688 ± 329 | 209.3 | |||
3A4 | 70.5 ± 3.7 | 3.09 ± 0.09 | 1.91 ± 0.2 | 21.9 | |||
E-10 hydroxylation | 2B6 | 98 ± 13.5 | 0.13 ± 0.01 | 1.33 | |||
2D6 | 4.75 ± 0.35 | 2.71 ± 0.06 | 373 ± 30 | 570.5 | |||
3A4 | 69.3 ± 9.7 | 0.4 ± 0.02 | 5.77 |
N-Demethylation by CYPs 1A2, 2B6, and 2C9, and E-10 hydroxylation by CYPs 2B6, and 3A4 were described by a Michaelis-Menten model (parameters Vmax and Kmdenoting the maximal rate at saturating substrate concentrations and the Michaelis constant, respectively). N-Demethylation by CYP3A4 was described by a Hill model (S50 denoting the substrate concentration at which 50% of the maximal rateVmax is reached, and A denoting the Hill coefficient). CYPs 2C8, 2C19, and 2D6 were described by a Michaelis-Menten model with uncompetitive inhibition by substrate (parameter Ks denoting the inhibition constant for uncompetitive inhibition by substrate).