*2.5. Inhibitors*

Drugs defined as inhibitors bind either to the active site or to an allosteric site of the enzyme. However, they can also bind to both; in these cases, the process is called "mixed inhibition" and can often be more potent than simple competitive or non-competitive inhibition. Inhibitors can be either substrates or non-substrates of the enzyme. As mentioned previously, non-substrate inhibitors typically bind to an allosteric site of the enzyme. If the inhibitor is a substrate transformed by the enzyme, the substrate itself or its metabolites could contribute to the inhibition mechanism. For example, studies on the inhibitory potency of gemfibrozil indicated that gemfibrozil is a potent inhibitor of CYP2C9 in vitro, but that it is a more potent inhibitor of CYP2C8 than CYP2C9 in vivo [5–7]. This observation is substantiated by several clinical reports of interactions between gemfibrozil and CYP2C8 substrates including cerivastatin, repaglinide, and glitazones [8–11]. The mechanism of this clinical interaction is explained by the formation of the major metabolite of gemfibrozil, gemfibrozil 1-O-β-glucuronide, which was found to potently inhibit CYP2C8 [10,12].

#### **3. Mechanism of CYP450 Inhibition**

Drug interactions due to drug metabolism inhibition are frequent since (1) CYP450-mediated metabolism is the major route of elimination for a large number of drugs, and (2) multiple drugs can compete for the same CYP450 active site. Mechanisms of CYP450 inhibition can be categorized as reversible (including competitive or non-competitive) or irreversible/quasi-irreversible (mechanism-based inhibition).

#### *3.1. Reversible CYP450 Inhibition*

Reversible inhibition is a result of rapid association and dissociation between the substrate drugs and the enzyme and can be categorized as competitive or non-competitive. A third category, uncompetitive inhibitor, also considered as a reversible inhibition type, is a very rare phenomenon and

will not be considered in this current review; this type of inhibitor binds only the enzyme–substrate complex, leading to a dead-end complex.
