Time Dependent Inhibition TDI

Time-dependent inhibitors, as the name suggests, inhibit DME in a time-dependent manner, that is, inhibition becomes more pronounced with prolonged exposure. Mechanism-based inhibitors are a subset of time-dependent inhibitors, for which a benign (or unreactive) inhibitor is activated (i.e., metabolized) by the DME resulting in inactive enzyme (Fig. 5.1). The concern over MBI is that the total active enzyme is decreased and de novo synthesis of the enzyme is required to return to the original enzyme activity levels. Therefore, compared to competitive inhibitors, mechanism-based inhibitors impact enzyme activity even after the inhibitor is no longer present. In vitro, typically only the time-dependent, co-factor dependent, and concentration-dependent nature of the inhibition is determined and in most cases this is sufficient (see criteria for determining MBI).

There are two classes of MBI: quasi-irreversible and irreversible.

1. In quasi-irreversible inhibition, a metabolite is formed that does not easily leave the active site of the enzyme, forming a metabolic intermediate complex (MIC) and temporarily disabling the enzyme. For example, the amino groups in eryth-romycin and troleandomycin are oxidized by CYP3A to form nitroso groups that coordinate to the iron, thus forming an MIC.

2. in irreversible inhibition, the substrate covalently binds to the enzyme or heme alkylation.

Moieties that could lead to MBI include, but are not limited to, methylenedioxy and alkenes, acetylenes, thiophenes, furans, and alkylamines. The formation of quinone methides also could lead to MBI (see the bioactivation section in Chap. 6).

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