Cytochrome p450 Interactions
CYTOCHROME P450 ENZYMES
In the liver, kinetic interactions predominantly involve CYtochrome P450 enzymes, CYP enzymes for short, which can be pronounced “sip”. Instead of concerning yourself with the origin of P450 nomenclature, take a moment to contemplate this picture of Ken (kinetic) taking a “sip” (CYP).
CYP enzymes, which reside primarily in the liver, make chemicals less lipid-soluble so they can be more easily excreted in urine or bile. Of over 50 CYP enzymes, six play a major role in the biotransformation of medications: 1A2, 2B6, 2C9, 2C19, 2D6 and 3A4. Our visual mnemonics will be built on the following phraseology:
The three most important CYPs are 1A2, 2D6 and 3A4. For psychiatrists, 2C19 can be important, while 2B6 and 2C9 are rarely significant.
A drug that is biotransformed by a particular enzyme is referred to as a substrate of that enzyme. When the substrate is biotransformed (metabolized) it is then referred to as a metabolite.
Each CYP enzyme can metabolize several substrates and most substrates can be metabolized by several CYP enzymes. Substrates are the “victims” of the interactions described in this chapter. Throughout this book we use the following visuals for CYP substrates:
“Aggressor” medications affect how long victim substrates linger in the blood, and the relative serum concentration of parent drug (substrate) to metabolite. For a given enzyme, interfering medications (aggressors) are either inDucers or inHibitors. InDucers stimulate (inDuce) production of metabolic enzymes. InHibitors interfere with an enzyme’s ability to metabolize other medications.
InHibition of an enzyme occurs when one drug (the inHibitor) binds more tightly to the enzyme than the victim substrate binds. 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.
Some (but not all) substrates are also competitive inHibitors of the same CYP enzyme.
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. Note that magnitude of inhibition tends to be dose-related over the dosage range of the inhibitor.
The opposite of inHibition is inDuction. InDuction occurs when an inDucer stimulates the liver to produce extra enzymes, leading to enhanced metabolism and quicker clearance of victim drugs.
The D is for Down, i.e., Decreased serum concentrations of victim substrates. Unlike inHibition (H for Hurried), inDuction is Delayed, not taking full effect for 2 to 4 weeks while we…wait for the liver to ramp up enzyme production.
InDucers will be depicted by:
More often than not, an inducer is itself a substrate of the enzyme. For example, carbamazepine (Tegretol) is represented as both an anvil and a fish.
The “shredders” are four strong inDucers of several CYPs, which cause countless chemicals to be quickly expelled from the body:
carbamazepine (Tegretol) - antiepileptic
phenobarbital (Luminal) - barbiturate
phenytoin (Dilantin) - antiepileptic
rifampin (Rifadin) - antimicrobial
Dr. Jonathan Heldt refers to the shredders as “Carb & Barb”
in his book Memorable Psychopharmacology.
St John’s Wort (herbal antidepressant) also inDuces several CYPs, but does so with less potency than the four shredders.
Can shredding be problematic even if the patient is not taking a victim medication? Consider this: