Why Some Statins and Grapefruit Do Not Mix

by Duane Graveline MD, MPH

When an individual takes a statin — by pill, tablet or capsule — it is broken down (metabolized) by enzymes in the liver and intestine. Statins, like most drugs, are dosed specifically for each patient in order to achieve the required therapeutic effect while minimizing any adverse drug reactions.

So any interruption of, or enhancement to, the metabolizing of the medication can alter the intended dose, sometimes dramatically. This can lead to unpleasant and, in extreme cases, even fatal consequences.

For their intended cholesterol lowering effect, all statins work in the same way — by HMG-CoA reductase inhibition — the metabolic pathway that, among other things, is responsible for the body’s production of cholesterol. How the body then metabolizes the drug, varies by statin type.

Some statins rely on the enzyme cytochrome P450 3A4 (CYP3A4) for this metabolizing to occur. The same CYP3A4 enzyme that breaks down these statins is disrupted by some citrus fruit, especially grapefruit. Grapefruit (whole pieces or in juice form) has been shown to be a potent inhibitor of the enzyme CYP3A4.1   

This effect of grapefruit on the enzyme responsible for metabolizing the statin, causes more of the medication than intended being absorbed, which effectively increases the dose. This increase in dose can have very serious consequences and cases of rhabdomyolysis caused by consuming grapefruit while on a statin have been reported.2 The main statins affected by inhibition of CYP3A4 are atorvastatin (Lipitor), simvastatin (Zocor, Simcor) and lovastatin (Mevacor).3

Whole grapefruit pieces or juice (freshly squeezed or frozen) will all interfere with the CYP3A4 enzyme. This doesn’t mean only avoiding taking a statin with grapefruit juice. As this effect of grapefruit on the metabolizing enzyme can last 24 hours, anyone taking a once (or more) a day medication that relies on this enzyme for normal breakdown of the drug should avoid grapefruit entirely.4

Statins that are not affected by CYP3A4 inhibition include pravastatin (Pravachol), rosuvastatin (Crestor) and pitavastatin (Livalo). No significant plasma elevation of these three statins occurs with CYP3A4 inhibitors like grapefruit.5

 

Although grapefruit is the best known example of a citrus interaction with drugs, it is not the only one. The actual interference with the CYP3A4 enzyme comes from organic compounds in the fruit called furanocoumarins.6 These furanocoumarins are present at varying concentrations in other citrus fruits and in some herbal medicines.

Examples of other fruits that contain furanocoumarins are limes and Seville oranges (commonly used for marmalade) — although grapefruit has the highest concentration. Sweet orange varieties, like navel and Valencia (those commonly available as whole fruit and used in fresh and frozen orange juice) do not contain furanocoumarins and therefore do not have the same enzyme suppressing effect.

It’s not just some statins that are affected by grapefruit. According to a report in the Canadian Medical Association Journal (CMAJ), more than 85 drugs are known or predicted to interact with grapefruit and 43 of these interactions can result in serious adverse effects. There is a list on the CMAJ site of drugs known to interact negatively with grapefruit along with the level of risk and dose related adverse event types.7

The CMAJ list covers a wide range of drug types including anti-cancer agents, anti-diabetic drugs, anti-infectives, anti-inflammatories, statins, cardiovascular drugs, central nervous system depressants and stimulants, immunosuppressant agents and others.

For each drug type, not all are compromised by grapefruit, so it is important to check which medications are affected. Some familiar names on the CMAJ list that are negatively impacted by grapefruit, to varying degrees, include the antibiotic erythromycin, sildenafil (brand name Viagra), tadalafil (Cialis), verapamil (for high blood pressure), diazepam (Valium), the pain medications fentanyl and oxycodone, clopidogrel (Plavix), tamsulosin (Flomax) and the immunosuppressant drug, ciclosporin (cyclosporine).

The grapefruit interaction effect with these drugs can be anywhere from mild to severe depending on many factors including the drug itself, the amount of grapefruit consumed and when the drug was taken.

Not all drug interactions with grapefruit are because the amount of the medication absorbed is increased. Grapefruit, along with some other fruits and fruit juices, can also affect the absorption of specific drugs, thereby lowering the received dose and reducing or completely blocking their effectiveness.

One example of a common drug that is not absorbed properly when grapefruit is consumed is the antihistamine fexofenadine (with many brand names worldwide including Allegra in the U.S.) that is used to relieve the symptoms of seasonal allergies.

It is important to remember that this negative grapefruit interaction affects only those individuals taking specific medications (always read the information sheet before starting a new prescription drug.)

For people that do not take these known medications, whole grapefruit remains an excellent source of vitamin C and a good source of dietary fiber, vitamin A, potassium and many other vitamins and minerals.

Mindful that a significant segment of the population can no longer enjoy grapefruit due to their medication regime, a team at the University of Florida has developed a grapefruit that has very low levels of furanocoumarins, the compounds that are believed to interfere with the CYP3A4 enzyme that metabolizes some statins and other drugs.

If human trials successfully confirm that medications are not adversely affected by this new hybrid grapefruit, very soon you may be seeing 'statin friendly' grapefruit on sale in your local supermarket.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

References:

  1. https://www.ncbi.nlm.nih.gov/pubmed/9548795
  2. http://www.neurology.org/content/62/4/670.short
  3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248744/
  4. http://www.ncbi.nlm.nih.gov/pubmed/8751023?dopt=Abstract
  5. http://www.ncbi.nlm.nih.gov/pubmed/17178259?dopt=Abstract
  6. http://www.ncbi.nlm.nih.gov/pubmed/14769198?dopt=Abstract
  7. http://www.cmaj.ca/content/suppl/2012/11/26/cmaj.120951.DC1/grape-bailey-1-at.pdf

April 2016
 


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