Inhibition of Cytochrome P450 enzymes

Excerpt from Cafer's Psychopharmacology, available soon from Amazon

ENZYME INHIBITION

InHibition of an enzyme occurs when one drug (the inHibitor) binds more tightly to the enzyme rather than a victim substrate. The inHibitor itself may be metabolized by the enzyme, or act as a non-competitive inhibitor. When an inhibitor is bound to an enzyme, the victim substrate must find another enzyme to metabolize it, or hope that it can eventually be excreted unchanged. Strong inhibitors may cause the victim substrate to linger longer, prolonging the victim’s half-life and elevating its concentration in the blood. For victim substrates that cross the blood brain barrier (as is necessary to be psychoactive), inhibition leads to increased drug concentration in the central nervous system.  

Why is H being emphasized? Well, when an inHibitor is added to an individual’s medication regimen, levels of victim drugs can escalate (H for High). InHibition takes effect quickly, within Hours (H for Hurried), although the effect may not be clinically evident for 2 to 4 days, until the victim substrate accumulates.

InHibitors of CYP enzymes will be represented by:

The magnitude to which an inHibitor increases the serum concentration of a specific substrate depends on the number of alternative pathways available to metabolize the substrate. If the drug is a substrate of, e.g., 1A2, 2D6 and 3A4, then inhibiting one of the three pathways should be of no consequence. Such substrates may be described as multi-CYP.

For a substrate metabolized by a single pathway, the effect of inhibition (and induction) will be dramatic. An example is lurasidone (Latuda), which is contraindicated with strong 3A4 inhibitors or inducers. 

Some inhibitors are stronger than others. In general, expect blood levels of susceptible substrates to increase in the ballpark of:

• mild inhibitor  ~ 25% - 50% increase
• moderate inhibitor  ~ 50% - 100% increase
• strong inhibitor > 100% increase

Expect these numbers to vary widely between substrates and individuals, often unpredictably. 

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