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Mechanism-based enzyme inhibition
Mechanism (or time) -based enzyme inhibition is associated with irreversible or quasi-irreversible loss of enzyme function, requiring synthesis of new enzyme before activity is restored.
The consequences of mechanism-based inhibition are:
- auto-inhibition of the clearance of the inactivator itself
- prolonged inhibition of the clearance of other drugs that share the same enzyme.
There may also be serious immunotoxicological consequences if a reactive intermediate is covalently bound to the enzyme. Therefore, screening of new compounds for mechanism-based enzyme inhibition is now standard practice within the pharmaceutical industry.
The prediction of the in vivo consequences of mechanism-based enzyme inhibition requires estimates of the maximum inactivation rate constant (kinact), the inactivator concentration associated with half kinact (KI), the concentration of the inactivator at the active site [I], and the first-order rate constant of the in vivo degradation of the enzyme (kdeg).
Values of kinact and KI are determined from appropriately designed in vitro studies (Ghanbari et al., 2006; Van et al., 2006; Yang et al., 2006;Yang et al., 2005). Within the Simcyp Simulator, the value of [I] is determined from the kinetic properties of the inhibitor and physiological parameters that modulate its input to both gut and liver. Simcyp provides values of kdeg for various CYPs based on meta-analysis of data from the literature.
The impact of mechanism-based inhibition on the amount of active enzyme is illustrated in Figure 12.
Figure 12. Simulated plasma concentrations of diltiazem, a mechanism-based inhibitor of CYP3A, during multiple dosing, and the corresponding decrease in active enzyme level.