As a fourth year engineering student, you would be safe to assume a couple of things about myself: first of all, I am horridly in debt with student loans, which makes all of my purchases limited to essentials only (that is to say things like food, soap, video games, pencils, you know the drill). As a result, it’s also been long since I’ve purchased any form of juice— after all, water is free and doesn’t make my teeth feel like they are swimming in sugar. However, it doesn’t distract me from the advisory warnings I see floating around on packaging– statements that pique my curiosity and send me into the realm of answer-searching.
The first came from an advisory statement I found on my father’s diabetes medication – “DO NOT TAKE WITH GRAPEFRUIT JUICE”. What an oddly specific exclusionary statement to make, when grapefruit (aside having a taste I can only describe as liquid disappointment) seems just as innocuous as any other citrus beverage, such as lemonade or orange juice.
The reason behind this warning is due to a group of chemicals found in grapefruit (as well as a few other hipster citrus, such as pomelos or hybrids like tangelos) called furanocoumarins. They are polyphenolic compounds which act as inhibitors to an enzyme present in your gastrointestinal tract. Cytochrome P450 3A4, affectionately called CYP3A4 like some sort of tag-along droid buddy, can be found snuggled up in your liver or small intestine, and makes a living oxidizing foreign chemicals in your body so they can be more readily excreted from your body. These foreign chemicals also include medicine taken orally, which makes CYP3A4 responsible for a large amount of deactivation of oral drugs.
Now pharmacists, clever as they are for your continued patronage, try to give you an amount of drug active ingredient that hopefully won’t result in your death. This means that they will give you enough drug to bypass intrinsic effects on the drug’s bioavailability (including the effects of CYP3A4) and still have a noticeable effect in treating your ailment, while not giving you too much to the point that your liver destroys itself trying to deal with the excess of drugs present in your bloodstream. Hooray!
But these so-called “safe” drug levels that they prescribe is assuming the person is a nice upstanding citizen, and doesn’t drink grapefruit juice unless they mistook it for pink lemonade. The furanocoumarins in grapefruit (be it in the fruit itself or in juice) irreversibly inhibit the enzyme, and at a surprisingly efficient rate— only 200 mL of juice can be enough to cause life-threatening enzyme inhibition, as way too much active ingredient enters the blood stream, bypassing the typical first-pass hepatic clearance. Effects of grapefruit inhibition are long-lasting too – it can take up to 24h to regain 50% of the enzyme’s typical activity, and up to 72h before the enzyme activity is back to normal, so it is not as simple of a solution as drinking your “Gee Jay” in the morning and pills at night.
Fortunately enough, this enzyme isn’t responsible for the reduction in bioavailability for all drugs. First of all, any drugs administered in a non-oral manner (i.e. topically or intravenously) will not be affected by CYP3A4, as they shouldn’t be in your gastrointestinal tract unless they somehow got super lost. But beyond that, the drug-enzyme interactions become more complicated, so it is easier to look at simply a list of drugs which have known interactions of bioavailability with furanocouramins. This includes benzodiazepines (a class of psychoactive sedatives), many amphetamines (including adderall and methamphetamine), methylphenidate (ritalin), many statins (drugs for treating cardiovascular disease), drugs for treating erectile dysfunction (such as sildenafil and tadalafil), certain off-market antihistamines, birth control hormones, and my dad’s diabetes medication. The full list, as you might imagine, is much, much larger – and not all drugs are affected equally, or even in the same matter. For some drugs the enzyme CYP3A4 actually has an activating effect, and so the intake of grapefruit juice in turn decreases their bioavailability.
However, it’s not all doom and gloom for the family disappointment of the fruit world. Research into potentially utilizing this mechanism in conjunction with drugs to increase their bioavailability and reduce costs is underway, and could reduce cost of medication. However, despite this phenomenon being known to the scientific community since the 1980s, variance in the impact of grapefruit-enzyme interactions between individuals has so far left these efforts unsuccessful.
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