TABLE 4

Kinetic parameters of the five inhibitors for the time-dependent CYP3A4 inhibition from human pooled liver microsomes and hepatocytes from two donors

Inhibitor and Conc. RangeHepatocytes
HLM
Donor 1
Donor 2
KIaKI, ukinactaKIKI, ukinactKIbKI, ukinact
μMmin1μMmin1μMmin1
CLA, 12.8–80 μM7.88 (3.09)7.640.040 (0.005)17.20 (2.80)16.860.028 (0.002)15.72 (3.52)5.090.063 (0.008)
DIL, 0.25–16 μM3.55 (1.33)3.120.027 (0.004)3.80 (0.59)3.380.014 (0.001)0.67 (0.2)0.550.019 (0.014)
ERY, 0.5–500 μM21.40 (4.60)20.030.016 (0.002)116.0 (6.10)108.580.055 (0.001)1.70 (0.49)1.480.017 (0.002)
VER, 0.31–20 μM2.99 (0.35)2.800.032 (0.001)2.58 (0.57)2.410.020 (0.001)3.50 (1.47)2.050.053 (0.007)
TAO, 0.05–1.6 μM0.56 (0.084)0.400.050 (0.004)1.05 (0.11)0.750.038 (0.002)0.19 (0.04)0.030.065 (0.004)
  • a KI and kinact of each inhibitor in hepatocytes and HLM (S.D. in parentheses) were obtained from nonlinear regression analyses of observed kobs values shown in Figure 2.

  • b KI, u values were calculated by KI multiplied by fu shown in Table 2. In addition to the KI values measured in the study, they were also reported in literature: CLA = 5.49 μM, 0.072 min−1 (Mayhew et al., 2000); DIL = 3.3 μM, 0.07 min−1 (Yeo and Yeo, 2001); ERY = 10.9 μM, 0.046 min−1 (McConn et al., 2004); VER = 2.9 μM, 0.15 min−1 (Yeo and Yeo, 2001); VER = 4.2 μM, 0.092 min−1 (Polasek et al., 2004); and TAO = 0.26 μM, 0.12 min−1 (Atkinson et al., 2005).