enzyme inhibition

Enzyme inhibition is the opposite of hiring workers — it is jamming the machinery. When one drug blocks a metabolizing enzyme, a second drug that depends on that enzyme is cleared more slowly, so its levels climb and its effects (and toxicity) intensify.

Most often an inhibitor competes for or directly blocks the active site of a cytochrome P450, reducing its catalytic activity. Because no new protein needs to be made, inhibition can appear quickly — within a dose or two — and reverses once the inhibitor is cleared, unless the inhibition is irreversible (mechanism-based, as with some macrolides).

Clinically, inhibition is a leading cause of dangerous drug interactions: ketoconazole, clarithromycin, ritonavir, and grapefruit juice can all raise the levels of CYP3A4 substrates to toxic ranges. The flip side is therapeutic — ritonavir is sometimes added deliberately to 'boost' other antiviral drugs by slowing their metabolism. For a prodrug, inhibition can instead reduce the formation of active drug and blunt its effect.