Originally published in The Ottawa Citizen November 30, 2004
Original Title is “Cytochromes: A Primer”

What is a drug interaction? Many believe it occurs when one or more medications directly affect the effectiveness of another. But how does it happen?

An understanding of the mechanisms that lead to this situation will enable the reader to ask a pharmacist pointed and specific questions about his or her prescription.

There are many seemingly random and chaotic lists of potential drug-drug interactions. Indeed, it can be an overwhelming proposition to try to list all of them.

Physicians, pharmacists and other health professionals need a logical evaluation of these interactions to sift out those that are clinically significant. To be clinically relevant, these interactions should be documented in humans, not animal studies.

For example, the blood-thinner warfarin (Coumadin) has to be consistently monitored and adjusted at times to maintain its anti-clotting effect. A drug that increases Coumadin blood levels can lead to an increased bleeding risk, and those that decrease blood levels increase the risk of a clot or stroke.

In this case, Coumadin has a narrow therapeutic range; dosing is incrementally adjusted over days to prevent wide swings in anti-clotting effect that could prove harmful to the patient.

Drugs can interact with four major body functions. They can alter how well drugs are absorbed by the intestine, change their breakdown and elimination rate (detoxification rate in the liver), reduce or increase the rate of excretion and elimination by the kidneys, and alter how well the drug spreads through the different body tissues and fluids.

Food and antacid use can delay intestinal absorption of medications. This is helpful especially for some medications that are absorbed too rapidly on an empty stomach; hence the recommendation to take with food.

Some antibiotics will eliminate some of the intestinal bacteria that will break down certain drugs such as digoxin, among others, possibly leading to toxic blood levels.

Why does grapefruit juice pose a problem? To understand this, a brief description of how the liver detoxifies the body is in order.

Most drugs are metabolized in the liver. Imagine the liver to be a giant biochemical processing factory. Within this huge factory, different departments specialize in processing specific drugs and toxins. Each department uses tools, designed to work on specific drugs, to complete its task.

The factory is called the Cytochrome P450 system. It is a complex mechanism that will use a variety of cytochrome enzymes (tools) to break down (metabolize) a variety of drugs. Indeed, a person’s genetic background can determine whether these cytochrome enzymes will be present in the liver.

Each of the cytochrome enzymes has a name that reflects its shape, structure and function; sort of like a set of wrenches and screwdriver bits.

If the enzyme is absent, the medication cannot be efficiently metabolized; people with this condition are termed poor metabolizers. It is as if that wrench and screwdriver set you bought at the hardware store to take apart that shelf is missing some sizes that you need; you now cannot dismantle it.

For example, one cytochrome called CYP2D6 is responsible for the breakdown of anti-depressants, codeine, statins (cholesterol medications) and beta blockers (used to treat hypertension). Five to 10 per cent of whites do not have this enzyme and thus cannot efficiently break down these drugs, whereas this occurs in less than one per cent in black and Asian populations.

These poor metabolizers can experience adverse side effects when given standard drug doses. Some people will not respond to codeine because they cannot metabolize and convert it to its active form, morphine, because they lack this cytochrome.

But genetics is only one way that someone becomes a poor metabolizer. Some medications and foods will block the activity of the enzyme, effectively deactivating it. Grapefruit is a prime example.

Grapefruit (juice) can affect a cytochrome called CYP3A for up to three days after ingestion. A standard dose of medications such as calcium channel blockers, among others, may result in a doubling of blood levels. This happens even if the grapefruit juice is ingested hours after dosing.

Indeed, grapefruit juice should not be part of the diet if someone is taking a medication metabolized by CYP3A.

Certain drugs can increase the rate of drug metabolism (drug breakdown). This process is called enzyme induction. Some patients will have to take a greater medication dose to achieve the same beneficial effect.

With your next prescription, your pharmacist or physician will be duly impressed when you ask them, “Does this medication affect the Cytochrome P450 system?” Even better, you will understand the answer.

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© Dr. Barry Dworkin 2004