Fig. 10. Time-dependent inhibition of P450 3A4 by indinavir (
Guengerich et al., 2020). (A) Conclusions about the stepwise inhibition of P450 3A4 with ketoconazole, clotrimazole, indinavir, itraconazole, and ritonavir (I in each case). E, E
‡, E´, and E* are conformationally distinct forms of the enzyme, P450 3A4. ESI is a complex containing both the substrate (S) and I but remains hypothetical at this time. The individual forms appear at the indicated times after mixing (23°C). (B) Time-dependent inhibition of 7-benzyloxyquinoline
O-dealkylation by indinavir with P450 3A4 (
Guengerich et al., 2020), with the indicated concentration of indinavir added at the start of the reaction. The y-axis indicates the fluorescence (F
410/510, arbitrary units) associated with the formation of the product (7-hydroxyquinoline). Note the delayed onset of inhibition in the first 50 s. Reprinted from J. Biol. Chem., Vol. 296, Guengerich, F. P., McCarty, K. D. and Chapman, J. G., Kinetics of cytochrome P450 3A4 inhibition by heterocyclic drugs defines a general sequential multistep binding process, page(s) 100223 (
Guengerich et al., 2020), Copyright (2020), with permission from Elsevier.
