What is it about grapefruit specifically that messes with pretty much every prescription in existence?
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Medicines are designed to account for the fact that some of the medicine will get broken down by your liver, so they have more medicine in them than you actually need. Grapefruits have a chemical in them that makes your liver less good at breaking down the medicine, so you end up with more in your system than you’re supposed to.
ANYTHING YOU EAT GOES THROUGH YOUR LIVER. It is called the “first pass” metabolism. Imagine once everything is broken down in your stomach, each molecule becomes a *car.* Your liver has lots of *highways* that run through it to bring *cars* to be metabolized. These different highways all have different “street names” like CYP 2E1(for alcohol) and CYP2D6(opioids and antidepressants). So depending on the type of *car*, it would fit on a specific highway. Grapefruit breaks down into a *car* that fits onto the highway CYP3A4. CYP3A4 is a MAJOR highway in your liver. Cholesterol medicine, antibiotics, blood pressure medication, and more all travel on it. So if Grapefruit travels on the highway with all the other *cars*, then there becomes a traffic jam, and the *cars* can’t go through the highway and get metabolized. This can create more side effects of other medications because your liver is busy metabolizing the Grapefruit *cars*.
Pharmacist here. Grapefruit produces some compounds which are metabolized (broken down) by a family of enzymes called CYP3A4 (cytochrome p450 3A4). If my memory serves me right, the compounds are called coumarins which are related in structure to the blood thinner warfarin. Basically if someone has enough grapefruit or it’s juices, the body’s CYP3A4 enzymes will now have to spend time breaking the coumarins down in addition to whatever drug also needs that enzyme to be degraded. Most drugs have both major and minor enzymes involved in their degradation, but the minor enzymes typically will take much longer to break down the drug as they are typically less efficient and break down the drug in less than an optimal fashion. This results in the drug of choice taking much longer to get broken down and removed from the body, resulting in a longer half-life.This means the amount of time the drug will carry out its effects on its target will be increased, sometimes 5-6x or even more (I can’t remember the specific drug, but do remember a drug with a 4-6 hour half life taking more than 5-6 days to leave the body because it’s metabolism was so dependent on the 3A4 complex with the minor enzyme because less than 10% as efficient as 3A4). To be fair it’s not every drug in existence (although I realize OP is speaking hyperbole), but it is a fair number of them – my guess is around 25-30% of drugs will rely on CYP3A4. Some of these will be highly effected while others just marginally slowed.
Edit: TL;DR – imagine leaving a city at 3am… you have no traffic to contend with. This is your 3A4 system without grapefruits compounds competing with whatever drug youve take that’s dependent on the 3A4 system for metabolism. Now imagine leaving the city at 430pm during rush hour traffic. This is akin to the drug of interest competing with the grapefruits compounds for enzymatic degradation.
When companies that develop medications calculate their dosages, one of the major things they have to take into account is bioavailability—how much of the drug actually ends up in your bloodstream after going through your digestive system.
The cytochrome P450 group of enzymes in your digestive system is a major factor in drug bioavailability. Grapefruits, for their part, contain a *lot* of furanocoumarins, which they use to protect themselves from fungus. When furanocoumarins meet cytochrome P450 enzymes, they *completely* wipe them out, and it can take your body upwards of *12 hours* to produce an entirely new batch.
So if you ingest a medication in that window of 12+ hours where those enzymes are nonfunctional, its bioavailability may end up being *many times* what the dosage was based off of. If, for example, the company developing the drug determined that it had *10% bioavailability* after digestion specifically due to cytochrome P450 enzymes, taking it with or in a huge window after eating grapefruit or drinking grapefruit juice will result instead in *100% bioavailability*—the equivalent of having taken a dose ***ten times larger***.
The Atlas Obscura article “[Grapefruit Is One of the Weirdest Fruits on the Planet](https://www.atlasobscura.com/articles/grapefruit-history-and-drug-interactions)” has more information on the process I’ve summarized here, as well as some fascinating details on the history of the fruit itself.
Intro: Most oral medications need to enter the bloodstream at a reliable concentration to work, something not too high for your body (causes toxicity) and not too low (causes loss of efficacy). There’s a lot biochemical players involved in shuffling drugs towards the bloodstream, a handful of which vary a ton between different individuals and lifestyles.
Answer: One compound in grapefruit juice IRREVERSIBLY inhibits a primary drug metabolizing enzyme within your intestines, CYP3A4. The enzyme normally breaks down drugs before they can enter the bloodstream, at a regular/predictable pace that can be accounted for during drug development. But if the enzyme suddenly gets knocked out, affected drugs cross into the bloodstream unchecked and cause some degree of overdosing. At least, until your body can produce a fresh batch of enzymes to overwrite that glass of grapefruit juice.
PS: It doesn’t even end here. Oral drugs also recirculate through your body. More and more of it should get broken down by enzymes and excreted from your body with each pass. The drug cross from the intestines into the bloodstream, from the bloodstream into the liver, and from the liver back into the GI tract — where it might encounter the impaired enzyme yet again. If someone keeps chugging grapefruit juice, the drug hangs around longer than intended and accumulates with each scheduled drug dose.
Related: Some other drugs (like Allegra) can only enter the bloodstream through a transporter channel in the intestines. Grapefruit juice also seems to inhibit this transporter, which can lead to drug underdosing and loss of efficacy.
LPT: Drugs can have potent interactions not only with other drugs, but also with different botanical foods and supplements — grapefruit juice happens to be super well documented, along with St. John’s Wort. Always check with your pharmacist to see what’s right for you.
[https://www.fda.gov/consumers/consumer-updates/grapefruit-juice-and-some-drugs-dont-mix](https://www.fda.gov/consumers/consumer-updates/grapefruit-juice-and-some-drugs-dont-mix)
I’m seeing a lot of partially correct answers, so I wanted to point out that there are multiple different mechanisms in which grapefruit can interfere with drug metabolism. All of them are caused by certain chemical compounds found in the citrus (called furanocoumarins). The three main ways they can do this are:
1. Inhibit metabolizing enzymes from breaking down the active form of the drug to the inactive form. This can lead to increased concentration of the drug in your body which can be toxic and lead to overdose (lots of drugs are affected this way, such as antidepressants and cholesterol medications)
2. Inhibit metabolizing enzymes from activating a prodrug to the active form of the drug. This can lead to decreased concentration of the functional drug in your body, reducing the drugs effectiveness. (Certain blood thinners are affected this way)
3. Blocks intestinal transport proteins from absorbing the drug from your digestive tract into your blood stream. This causes the drug to pass through your body without being absorbed, reducing the drug’s effectiveness (Allegra is affected in this way)
For mechanisms 1 and 2, if only small amounts of grapefruit is consumed, only the intestinal metabolic enzymes are affected, meaning that only drugs taken orally would be impacted. If lots of grapefruit is consumed, liver enzymes are also affected, which means that drugs taken via any administration method are impacted.
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When you ingest a medication it has to be broken down. Your liver has enzymes to do that, called cytochrome P450 (CYP450). There’s different types CYP450, but the most common one that break down a lot of medications (but not “every prescription in existence” though) is called CYP3A4. Grapefruit, in very large quantities, inhibits CYP3A4 from doing its job. Medications that need CYP3A4 to be metabolized and broken down will now stay in your system, build up and potentially increase the risk of toxicity/adverse effects.
Your body gets rid of medications in two main ways (there are others but these are the main two): pee them out or process them in your liver so the medications are inactivated and then pee or poop the inactivated medications out. There are a collection of enzymes in your liver (enzymes are kind of like fuel that powers the inactivation process) that modify medications so that they are inactivated. These enzymes can be turned up by some substances and can be turned down by others. Grapefruit is one of the substances that turns the enzymes down. So your body can’t clear medications as quickly -> you grt higher levels of medications in your body -> toxicity can occur.
Source: final year med student
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