TABLE 2

Inhibition of CYP3A activity by DPC 681 and ritonavir in human and rat liver microsomes as measured by testosterone 6β-hydroxylation


Parameter

Human CYP3A4

Rat CYP3A
DPC681
Ritonavir
DPC 681
Ritonavir
IC50 (μM)a 0.039±0.006 0.010±0.001 1.616±0.020 0.070±0.010
KI (μM)b 0.240±0.040 0.038±0.005 N.D. N.D.
kinact (min-1)b
0.220±0.060
0.290±0.010
N.D.
N.D.
  • N.D., not determined

  • a IC50 was obtained in the presence of DPC 681 or ritonavir at concentrations of 0, 0.002, 0.0078, 0.031, 0.13, 0.5, and 12.5 μM. Samples were prepared in triplicate

  • b Mechanism-based inactivation was performed in the presence of DPC 681 or ritonavir at concentrations of 0, 0.031, 0.13, 0.5, 2, and 8 μM, and with preincubation of 0, 3, 7, 13, and 25 min in the presence of 1 mM NADPH. Samples were prepared in triplicate