Figure 2
Time-dependent inhibition of CYP3A by the ten tested inhibitors in human liver microsomes (HLM). KI and kinact values of the inhibitors (crizotinib, diltiazem, erythromycin, imatinib, nefazodone, nilotinib, pazopanib, roxithromycin, telithromycin, verapamil) were determined in pooled HLM with midazolam 1′-hydroxylation as the marker reaction for CYP3A activity. The rate of inactivation of CYP3A activity by each inhibitor concentration (kobs) was determined by linear regression analysis of the natural logarithm of the percentage of activity remaining versus preincubation time data for each drug (inserts). The KI and kinact were then calculated by non-linear regression analysis of the kobs versus inhibitor concentration. The incubations were carried out in triplicate, and the results are given as mean ± standard deviation. KI, inactivation rate constant; kinact, maximal inactivation rate; Kobs, initial inactivation rate.
