Ketoconazole selective enzyme inhibition

The importance of these enzymes for drug interactions is that enzyme inducers and inhibitors may preferentially affect certain isoforms and consequently may only affect the metabolism of selected drugs. For example, ketoconazole has the potential to inhibit the metabolism of drugs metabolised to a great extent by the sub-family 3A (e.g. midazolam) but not of those metabolised by sub-family 1A (e.g. theophylline), 2C (e.g. diazepam), or 2D (e.g. metaprolol). In contrast, although fluconazole is a weaker inhibitor of the sub-family 3A than ketoconazole, it also inhibits the sub-family 2C, and so the interactions of fluconazole differ from those of ketoconazole. 

Mechanism of Action. Ketoconazole selectively inhibits certain enzymes that are responsible for the synthesis of important sterols in fungal cells.9 A deficiency of sterols results in impaired membrane function and other metabolic abnormalities within the fungal cell. At higher concentrations, ketoconazole may also directly disrupt the cell membrane, resulting in the destruction of the fungus. 

Ketoconazole was the first oral azole introduced into clinical use. It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome P450 enzymes that is, it is less selective for fungal P450 than are the newer azoles. As a result, systemic ketoconazole has fallen out of clinical use in the USA and is not discussed in any detail here. Its dermatologic use is discussed in Chapter 61. 

Chemical/Antibody Inhibition The selectivity of chemical inhibition for cytochrome P450 inhibitors is often dependent on inhibitor concentration. For example, ketoconazole is a potent and selective inhibitor of CYP3A enzymes at 1 xM concentration, whereas at higher concentrations it also inhibits CYP2C8 and other enzymes. A list of selective chemical cytochrome P450 inhibitors is shown in Table 15.1 (Tucker et al., 2001). Note that in... 

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