Introduction

Can something in grapefruits really affect how a medication works in our body? The answer is yes, yes it can. For a lot of medications, you can find a warning on the label stating that you should avoid grapefruit while you’re taking it.

Basically, drugs are designed to work on patients at a certain dose that’s been established through various experiments and trials. We are very complex organisms and we have a lot of other biological processes going on inside of us, so these established doses assume that everything else in your body is working normally. This assumption includes the fact that the drug’s natural breakdown in your body is happening at a regular, expected rate, so that whatever’s left of the drug after all that processing is going to do its job.

Grapefruit messes with one of those “drug processing” steps!

CYP3A4

Drugs are being chemically altered in your body as you take them. This is called drug metabolism. They don’t necessarily stay in the exact chemical structure that they were initially. Enzymes all throughout your body start reacting with the drugs and changing their structure, usually so the drugs become easier for your body to eliminate down the line. One of those very important enzymes that handles and actually bio-inactivates 50% of all drugs we take is Cytochrome P450 3A4 (CYP3A4).¹

CYP3A4 oxidizes drugs, adding oxygen atoms to the drug’s structure.² Adding oxygen atoms makes the drug more polar, and this makes it so that the transformed drug is more likely to be absorbed into the bloodstream and ultimately excreted.³ Essentially, your body is ready to protect you from whatever compounds enter, and CYP enzymes (and other metabolic enzymes like CYP!) are ready to transform those compounds into things that the body can more easily excrete. There are actually 57 genes that have been identified that code for various CYPs in humans.⁴

CYP3A4 is generally found in two places: the cells lining the small intestine/colon, and the parenchymal cells of the liver.⁵ An orally administered medication is going to encounter and be processed by CYP450 in the intestines first, and another time in the liver, before it enters the circulation.

It’s also possible that CYP3A4 is necessary to activate drugs after being taken. In this case, the medication taken is called a prodrug; it’s not in its “final form”. We rely on the CYPs in our bodies to turn those prodrugs into the active form, and then they can perform their therapeutic functions.

Furanocoumarins in Grapefruit

There are compounds in grapefruit called furanocoumarins. Furanocoumarins in grapefruits are one of the main culprit compounds in preventing CYPs from doing their job. When you ingest grapefruit in the form of fruit or juice (a glass of juice has been shown to do the trick), the furanocoumarins encounter the CYP3A4 enzymes in the small intestine, just like other ingested drugs do. CYP3A4 turns the furanocoumarins into a reactive intermediate that bonds covalently to the active site of the CYP3A4 enzyme, irreversibly inhibiting it.⁵ Examples of furanocoumarins that do this are bergamottin⁶ and 6’7′-Dihydroxybergamottin.⁷

This leads to a decrease in the unaffected, functional CYP3A4 enzymes in your small intestine for a long time; studies show the effects of ingesting grapefruit juice can last several days.⁸ If we put two and two together, we can see that the drugs that are supposed to get broken down won’t be, and that will lead to a much higher amount of drug present in the body than expected. In addition, prodrugs that are supposed to be activated by CYP3A4 will not be activated, lowering their efficacy.

Some Affected Medications

Statins

Statins are a category of cholesterol medications and they control the production of cholesterol in your body.⁹ However, if your statin levels are too high, it can lead to a condition called rhabdomyolysis, which is the breakdown of muscle.^10,11 Simvastatin (Zocor), Lovastatin (Mevacor), and Atorvastatin (Lipitor) are some statins that have been shown to be elevated in the body due to grapefruit juice inactivating CYP3A4.¹² One study has shown that taking a glass of grapefruit juice at the same time as taking Simvastatin or Lovastatin made their levels go up in the blood by 260%, and levels of Atorvastatin were observed to go up by 80%.¹³

Blood Pressure

Although not all blood pressure drugs are affected by grapefruit, there are a handful that are. Nifedipine (Procardia, Adalat CC), Felodipine, Losartan, and Eplerenone have been observed to be affected by grapefruit juice. One study has shown that a patient who took Nifedipine, which is a calcium channel blocker, along with grapefruit juice, experienced a rapid decrease in blood pressure.¹⁴ Another study of 16 participants found that grapefruit juice interferes with Nifedipine metabolism and slows down gastric emptying, and that the inhibition of Nifedipine metabolism is likely occurring at the secondary oxidation step.¹⁵ In addition, Lotarsan, which is an angiotensin II antagonist, is converted into its metabolite, E3174 by CYP3A4, and a study found that grapefruit juice blocks that. This leads to lowered ability for the active metabolite, E3174, to control blood pressure.¹⁶ 

Mood Medications

A lot of anti-anxiety drugs and antidepressants aren’t affected by grapefruit, but according to the FDA, buspirone (BuSpar) is one that shouldn’t be combined with grapefruit.¹⁷ Another is triazolam, which is a benzodiazepine hypnotic. Grapefruit juice ingestion has been shown to increase the levels of triazolam in the blood by 96%,¹⁸ and affected the subjects’ ability to perform in the digital symbol substitution test (DSST), which is a test for cognitive function in clinical neuropsychology.¹⁹

Heart Rhythm

Amiodarone is an anti-arrhythmic, and is metabolized by CYP3A4 into N-DEA. In a study of 11 healthy individuals, ingestion of grapefruit juice completely inhibited the formation of N-DEA, showing that the CYP3A4 metabolism of amiodarone was severely blocked. This led to a decrease in the alterations that taking amiodarone has on PR and QTc intervals.²⁰

Antihistamines

Fexofenadine (allegra) has been well-studied in the context of grapefruit juice intake and CYP3A4 activity. This is one of the drugs that actually get decreased in bioavailability when taken with grapefruit juice, rather than becoming excessive. In a randomized crossover study, grapefruit juice was found to decrease the oral bioavailability of fexofenadine.²¹

Conclusion

Grapefruits contain compounds called furanocoumarins, and some of them have been shown to block the ability of Cytochrome P450 3A4 (CYP3A4) to metabolize drugs. Some drugs are designed so that even though a percentage of the dose is metabolized by CYPs, the rest of it will be intact enough to achieve the therapeutic effect. Other drugs are prodrugs, and need CYPs to be metabolized and turned into the active drug. The furanocoumarins in grapefruit juice have been shown to irreversibly block the active site of the CYP3A4. This leads to drugs being too abundant in the body leading to adverse effects, or drugs not being activated and therefore not delivering the intended therapeutic effect.

There are other compounds out there that have similar effects, such as St. John’s wort,²² tobacco,²³ starfruit juice,²⁴ and watercress.²⁵ There are different extents to how well they’ve been studied. When you start looking into toxicology and the intricate relationships between various food items, ingredients, and enzymes, it can get pretty overwhelming. It’s important to remember that science is an ever-changing field, with new discoveries and updates being assessed and interpreted on a regular basis.

Have you been warned about consuming grapefruit products? Are you thinking about your own medications now, wondering if that’s something to look out for? If you’re on any medications and want to know if you should avoid grapefruit products, chances are you were informed of this by your doctor at the time of prescription. You can also ask your pharmacist for information, if you want to double check. Listen to your doctor (or multiple doctors) and trust their directions when it comes to medications you are on and the things to avoid while on them.