Table 1

Unbiased kinetic parameters of amitriptyline biotransformation by lymphoblast-expressed human CYP isoforms

PathwayCYPKm1-aS501-aVmax1-bAKs1-aClint1-c
N-Demethylation1A21-d 63.5  ± 18.91.79  ± 0.2328.2
2B656.7  ± 8.80.25  ± 0.014.4
2C89.74  ± 3.40.7  ± 0.1370  ± 24.471.9
2C91-d 50.5  ± 10.23.97  ± 0.3278.6
2C198.52  ± 1.34.22  ± 0.2639  ± 131495.3
2D67.12  ± 0.61.49  ± 0.031688  ± 329209.3
3A470.5  ± 3.73.09  ± 0.091.91  ± 0.221.9
E-10 hydroxylation2B698  ± 13.50.13  ± 0.011.33
2D64.75  ± 0.352.71  ± 0.06373  ± 30570.5
3A469.3  ± 9.70.4  ± 0.025.77

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).

  • 1-a  Values in micromolar concentration.

  • 1-b  Values in picomoles per minute per picomole of CYP.

  • 1-c  Intrinsic clearance in nanoliters per minute per picomole of CYP.

  • 1-d  Velocities at amitriptyline concentrations greater than 167 μM excluded in estimation of kinetic parameters.