TABLE 1

Estimated inactivation parameters of CYP3A4 by verapamil and its metabolites

Enzyme
Inhibitors
kinact a
K1 a
kinact/K1
fu,m b
kinact/K1,u
min-1 μM min-1·nM-1 min-1·nM-1
Pooled human liver microsomes S-Verapamil 0.13 ± 0.01 1.39 ± 0.18 93.53 0.84 111.40
R-Verapamil 0.08 ± 0.01 5.10 ± 1.63 15.31 0.68 22.51
S-Norverapamil 0.27 ± 0.01 1.64 ± 0.27 164.63 195.99c
R-Norverapamil 0.17 ± 0.01 2.97 ± 0.67 57.23 68.13c
R,S-Norverapamil 0.21 ± 0.01 2.11 ± 0.25 97.45 0.84 116.01
Recombinant human CYP3A4 S-Verapamil 0.64 ± 0.04 2.97 ± 0.30 215.49 0.69 312.3
R-Verapamil 0.39 ± 0.06 6.46 ± 2.19 60.37 0.68 88.78
R,S-Norverapamil 1.12 ± 0.08 5.89 ± 0.83 190.15 0.67 283.81
R,S-Verapamil 0.43 ± 0.09 4.57 ± 2.00 94.09
D617
0.07 ± 0.00
7.93 ± 0.45
8.52

  • ↵ a ± standard error of the parameter estimated

  • ↵ b fu,m, free fraction of the drugs in the microsomes

  • ↵ c We assumed that fu,m for R- and S-norverapamil were the same as that of racemic norverapamil