In Vivo Prediction of DDIs for Mechanism Based Inhibitors

Mechanism-based inhibitors inactivate DMEs; therefore, the enzyme has to be resynthesized in order to recover to its original activity. In the liver and intestine, there is a constant rate of enzyme synthesis (ksyn) and enzyme degradation (kdeg). In the absence of a mechanism-based inhibitor and at steady-state, ksyn = kdeg. In the presence of a mechanism-based inhibitor, the total enzyme degradation rate is increased from its natural rate (kdeg) by kinact. The net result is a transient decrease in the total active enzyme concentration. The time it takes for the enzyme to recover to its original enzyme level depends on the de novo synthesis rate, which is different for each isoform and depends on the organ (liver versus intestine).

DDI magnitude (AUQ/AUC) in the presence of an MBI is determined using the following equation (based on Mayhew et al. 2000):

fm = fraction of the substrate metabolized by the enzyme [I] = inhibitor concentration

KI = concentration of inactivator (or inhibitor) at 1max/2

kinact = first-order rate constant for the formation of inactivated enzyme kdeg = rate constant for the natural rate of degradation of the enzyme (Table 5.10).

Table 5.10. Half-life and kdeg of human hepatic CYP isoforms and intestinal CYP3A4

P450 isoform

Half-life (h)

kdeg (h-1)

CYP1A2

36-105

0.0066-0.01926

CYP2B6

32

0.0217

CYP2C8

23 (8-41)

0.0301 (0.0169-0.0864)

CYP2C9

104

0.00666

CYP2C19

26 (7-50)

0.0266 (0.0139-0.099)

CYP2D6

51, 70

0.0136, 0.0099

CYP3A4

44-140

0.00495-0.0158, 0.0077

CYP3A5

36 (15-70)

0.0193 (0.0099-0.0462)

CYP3A4 (intestinal)

12-33

0.021-0.0578

All the data based on Yang et al. (2008) except for CYP3A4 of kdeg = 0.0077 h-1 from Wang 2010

All the data based on Yang et al. (2008) except for CYP3A4 of kdeg = 0.0077 h-1 from Wang 2010

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