Grapefruit: Forbidden fruit or juice or both?

A few years ago, a patient asked me if I knew anything about grapefruit juice and drug interactions. I told him truthfully that I'd heard of a few case reports and some theories that floated around from time to time. "It is probably better to just avoid grapefruit juice altogether," I said. As Shakespeare would have aptly put it, "His countenance fell," because he loved grapefruit and loudly lamented he'd "greatly miss it." I told him to at least wait a few hours after he took his morning meds to partake of any components of the fruit. With the latest information on drug-grapefruit interactions, depending on which medications he was taking, this was really bad advice.

The grapefruit-juice "effect" can last up to 72 hours. I wish I'd known 20 years ago what I know now, but questions still linger. Does ingesting a grapefruit amount to the same interaction as drinking the juice? It seems that the juice would represent a more toxic cocktail of furanocoumarins, which are the nasty little compounds found in grapefruit as well as Seville oranges and limes, that inhibit the concentration of cytochrome p450 3A4. The latest report suggests that the effects can range from complete nullification of a drug effect as in clopidogrel to boosting the effects of the drug simvastatin to as much as 330% in the human bloodstream.

Perhaps it was a grapefruit that Eve presented to Adam. Hmm . . .

The ramifications of this finding are clear. Who knows how many GI bleeds in the warfarin-rivaroxaban trials were due to grapefruit ingestion? Were early compounds yearning for market relegated to the boneyard because of grapefruit-juice–induced toxicity? Did my colleague get sued over statin myopathy because her patient suddenly developed a hankering for grapefruit? Did my patient develop pulmonary toxicity while on amiodarone because his wife bought grapefruit juice for a month because she thought it might be good for him? One will never know, but one should get the hint. We clearly need to warn our patients of this interaction, and trials need to be controlled for grapefruit ingestion when compounds are tested.

There is a smattering of short case reports in the literature describing the grapefruit-drug interaction. In 2009, a report was published in the Southern Medical Journal that described verapamil toxicity in a 42-year-old female who had consumed large amounts of grapefruit juice. In the Annals of French Anesthesiology in 2009 there was a report of a patient who hemorrhaged profusely after taking her vitamin-K antagonist with grapefruit juice.

It is uncertain as to whether the same concerns hold for ingesting the actual fruit as they do for the juice of the grapefruit. In 2010, in Clinical and Experimental Hypertension, a report was published in which a hypertensive male was given 7 oz of grapefruit juice with nifedipine and later with amlodipine. There was no change in plasma concentration of the amlodipine, but the nifedipine concentration increased significantly and resulted in "short-lived" hypotension. Interestingly, they repeated the experiment with ingestion of the actual grapefruit, with no resultant change in concentration or blood pressure.

For now, there are enough data to support the recommendation for banning grapefruit and grapefruit juice altogether from the diets of those on certain cardiovascular medications. For laypersons who read my blog, I'll add the names under which these compounds are marketed. (For a more complete list, check abcnews.com.) They include:

Rhythm agents:

• Amiodarone (Pacerone).
• Dronedarone (Multaq).
• Quinidine (not commonly prescribed).

Cholesterol agents:

• Atorvastatin (Lipitor).
• Lovastatin (Mevacor).
• Simvastatin (Zocor).

The new anticoagulant rivaroxaban (Xarelto), prescribed in placed of warfarin in some.

High-blood-pressure meds:

• Nifedipine (Procardia).
• Verapamil (Verelan).
• Felodipine (Plendil).

Antiplatelet agents:

• Ticagrelor (Brilinta).
• Clopidogrel (Plavix)—in this case, it completely nullifies the effect of Plavix instead of exaggerating it, as in the other meds listed above.

In addition, there is an interaction with the heart-failure diuretic eplerenone (Inspra).

I note that sirolimus is also listed here, and I'm curious about patients with stents coated with sirolimus (the older Cypher stents), but I don't know of any data or case reports that directly address this issue.

So, all around the world, when medical practitioners open the office door today, we'll get many questions about grapefruit. Until this week, it simply sat nestled in grocery aisles and holiday fruit baskets, waiting to be lovingly sliced as citrus-laden droplets spray our faces and our taste buds prepared to bask in the glory of its bitter sweetness. It only suffered from unsubstantiated rumors and gossip mongering. But today, we know more. Did the English poet John Milton perhaps know then what we know now when he penned this phrase many years ago? "The fruit of the forbidden tree whose mortal taste brought death into the world and all our woe."

Alas, until more data are available, my lowly grapefruit, "I must banish thee."

Your comments

	Grapefruit: Forbidden fruit or juice or both?
	# 1 of 25	December 5, 2012 12:00 (EST)
	Smith	All of the above medications have side effects, even wiithout grapefruit juice.  Maybe it's time to adopt asprin, diet and exercise as the principal cardiac medicines and embrace the grapefruit and its juice, which is loaded with benefits and no side effects.  First do no harm!
	# 2 of 25	December 7, 2012 12:01 (EST)
	Don Kelsey	More on enzymes I'm a bit surprised by this blog since pharmacy warnings about grapefruit have shown up with Lipitor Rx for years. However, perhaps it is useful to remind people that drug /food / enzyme interactions are very serious. A useful website is http://www.drugbank.ca/drugs?type=approved, which not only lists specific drug and food interactions, but also lists the enzymes involved, e.g. Cytochrome P450 3A4 listed first for Lipitor. Incidentally, grapefruit doesn't affect the actual "concentration" of the enzyme. It inhibits or blocks the enzyme sites, so it cannot metabolize avortastatin. So, grapefruit (and lots of other drugs) affects the availability of free enzyme sites. A commonly overlooked interference is Prilosec, which also affects p450 3A4. At least in my experience, this doesn't show up on pharmacy warnings. However, taking Prilosec and some similar meds should be avoided with the same list of medications listed above. With regard to the "study" comparing juice with fruit, there is no logical reason to assume that the biochemical effects of juice and juice can be different. There might be a difference in amount consumed, since a glass of juice would be equivalent to eating several fruit (and most people eat only 1/2 or 1 grapefruit at a time). An unscientific "study" involving one person or even a few subjects cannot be rationally considered as relevant one way or the other. Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 3 of 25	December 7, 2012 12:04 (EST)
	John Horn	Grapefruit juice and stents Since grapefruit juice only inhibits CYP3A4 in enterocytes, unless you eat the stent, there will be no possible interaction. Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 4 of 25	December 7, 2012 01:56 (EST)
	michael schwenk	Grapefruit or grapefruit juice I re-read your article and can still find no evidence that grapefruit, as opposed to grapefruit juice, would cause these interactions. In fact you even mention a challenge with grapefruit producing negative results in a patient who had an interaction with grapefruit juice. Depending upon the size of the grapefruit, I'm not sure how much juice would be contained in it. Sounds like a simple crossover study should be done comparing CYP3A4 inhibition with juice or fruit consumption, before proscribing fruit consumption. Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 5 of 25	December 7, 2012 05:50 (EST)
	Jolanta Calusinska	Qestion to the author Excuse me. Did I miss something? What is the basis of thesis: "complete nullification of a drug effect as in clopidogrel". Would the author, please, send me any link to any medline article/FDA statement concerning with it? Kind regards JC Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 6 of 25	December 7, 2012 08:25 (EST)
	Melissa Walton-Shirley	Jolanta American Journal of Cardiovascular Drugs 2004, Baily et al. This suggests "attentuation" of the drug effect but there were others. I'll try and locate them. Promise, didn't make it up! Thanks for your inquiry. Melissa Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 7 of 25	December 7, 2012 08:34 (EST)
	Melissa Walton-Shirley	Here's another Bailey, D.G Arnold J Grapefruit and medication interactions-Forbidden Fruit or avoidable consequences CMAJ 2012; DOI;10.1503/cmaj 120951 Hope that helps! Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 8 of 25	December 9, 2012 11:09 (EST)
	arland adams	internal medicine There is no drug prescribed, or over the counter availability, that may not have a possible side effect. I advise my patients: we,I and the patient, must weight the benefit against the possible side effect. The nutitional benefits of grapefruit sections for breakfast,something I have enjoyed daily for 50 years, should be considered. The studies reported on the adverse effects of this fruit, to my knowledge, have been done with the ingestion of large quantities of the juice. Author's disclosure (Dec 9, 2012) Currently in practice of medicine at age 85 and an avid golfer.
	# 9 of 25	December 10, 2012 08:05 (EST)
	Rusvel Gómez	Don´t forget codeine A lot of medication for pain relief and cough include codeine (In Latin American but I don´t know about other countries). It can induce exaggerated morphin effects when is betrothed with gapefruit juice. Author's disclosure (Dec 10, 2012) I have no relevant disclosures to make in connection with this topic.
	# 10 of 25	December 10, 2012 08:10 (EST)
	Rusvel Gómez	Don´t forget codeine A lot of medication for pain relief and cough include codeine (In Latin American but I don´t know about other countries). It can induce exaggerated morphin effects when is betrothed with gapefruit´s juice. Author's disclosure (Dec 10, 2012) I have no relevant disclosures to make in connection with this topic.
	# 11 of 25	December 10, 2012 10:24 (EST)
	Jolanta Calusinska	qestion to the author contitnuing I am not saying you've made it up. I am really interested if such an interaction really exists. 1) If grapefruit juice completely nullificates a drug effect in clopidogrel it do should be stated in FDA/EMEA warnings! 2) If I found proper paper to make an evidence to prove it I can ask my boss to start asking patients not to drink grapefruit juice when using clopidogrel. Otherwise she would just smile and make a circle over her temporal with her index finger (meaning I must be a kook) In "Interactions Between Grapefruit Juice and Cardiovascular Drugs:by : David G. Bailey; George K. Dresser I have found: "or attenuated antiplatelet activity with clopidrogel" which is, in my opinion, a little far from:"complete nullification of a drug effect as in clopidogrel" So I am still waiting for evidence Jolanta Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 12 of 25	December 10, 2012 05:10 (EST)
	Julian Pearce	David Bailey interview here is a link to a recent interview with David bailey on the matter (or you can stream the audio) Author's disclosure (Dec 10, 2012) I have no relevant disclosures to make in connection with this topic.
	# 13 of 25	December 10, 2012 05:13 (EST)
	Julian Pearce	David Bailey interview I'm not sue why my post above won't show the URL for the interview I was referring to! Google David Bailey ABC health report and you will locate it. Author's disclosure (Dec 10, 2012) I have no relevant disclosures to make in connection with this topic.
	# 14 of 25	December 10, 2012 08:16 (EST)
	Lisa Zaretzky	Clopidogrel & Grapefruit Interaction?? I've looked up 3 sources and I cannot find that this interaction exists. What is the evidence?? Author's disclosure (Dec 10, 2012) I have no relevant disclosures to make in connection with this topic.
	# 15 of 25	December 12, 2012 06:56 (EST)
	Giovanni Gulli	I just can't help asking Dear Dr Walton-Shirley, talking vegetables, no heartfelt comment on the antihypertensive effect of flaxseed? (Merry X-mas & HNY!) Author's disclosure (Dec 12, 2012) I have no relevant disclosures to make in connection with this topic.
	# 16 of 25	December 12, 2012 10:04 (EST)
	Will Clementi	1984 Interactions with grapefruit juice and drugs have been described for decades. Some reports suggested that that amount of juice required to inhibit or affect a CYP system was large. And yet, the above article does discuss the quantitative aspects of possible interactions in vivo. It remains remarkable that health care professionals seek to alarm patients and other providers with data that are not new. From my experience, most people do not consume grapefruit daily as they would coffee for example and it is likely that what is in the can differs from what is in the fruit. And most people do not drink 8 oz or 16 oz of grapefruit juice from a can. A fruit most people do not eat more than once a day. "Alarm" articles may draw more readers but such articles do little advance our understanding or sharing of information. I would have much preferred a description that relied on quantitation and less on "grapefruit anxiety." Author's disclosure (Dec 12, 2012) I have no relevant disclosures to make in connection with this topic.
	# 17 of 25	December 12, 2012 04:13 (EST)
	Melissa Walton-Shirley	Will I assure you the goal of this article is not to "draw readers". As a full time cardiologist in private practice, I implement information as I receive it. Though I've been aware of an occasional concern with grapefruit juice, the degree of information on this issue us growing. It's not a minor concern. To trivialize this issue would be a disservice to my patients. Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 18 of 25	December 12, 2012 09:32 (EST)
	Daniel Weiss	I remain highly skeptical First I must say that I have not yet been able to read the recent CMAJ paper although I familiar with Bailey's previous publications. Next, I would urge Dr Walton-Shirley to provide specific references when firm claims are made. I try to do this in my blog posts with hyperlinks as I did when I addressed the grapefruit issue in Dec 2011 on my post at Readers can then study the paper and draw their conclusions. Second this is a complex area since grapefruit can affect OAT1A2 a transporter protein which can reduce uptake of drugs into cells and as well can affect P-glycoprotein which involves efflux of drugs from cells. In addition, ,many studies were done with huge amounts of grapefruit or drug. Furthermore, there are exceedingly few reports of clinically significant episodes clearly due to grapefruit. Finally, we can often monitor biologic effects on patients and PK studies with single doses may or may not be clinically important. So I think we ought to be alert to this effect and should have patients avoid grapefruit when receiving immunosuppressants, HIV drugs or chemotherapy. But I am not so sure about the clinical significance of other drugs. By the way, I found nothing on PubMed searching grapefruit and rivaroxaban and clopidogrel and grapefruit. Author's disclosure (Dec 12, 2012) I have no relevant disclosures to make in connection with this topic.
	# 19 of 25	December 12, 2012 09:35 (EST)
	Daniel Weiss	My blog post on grapefruit and statins My blog can be found if you google Dr Dan Weiss blog or drdanshealthandhormones. Look for the grapefruit folder. Links are routinely removed from comments, it appears. Author's disclosure (Dec 12, 2012) I have no relevant disclosures to make in connection with this topic.
	# 20 of 25	December 12, 2012 10:22 (EST)
	Harry Hawthorne	Grapefruit juice Grapefruit juice specifically inhibits the CYP3A4 site in the small bowel. Four ounces of juice with inhibit these sites for about a week. Author's disclosure (Dec 12, 2012) I have no relevant disclosures to make in connection with this topic.
	# 21 of 25	December 13, 2012 06:55 (EST)
	Melissa Walton-Shirley	Daniel Blogs are most usually opinion pieces. Occasionally, I cover something aired in the national news as I did this topic. There are lots of references available on grapefruit juice that are pretty easily found on pubmed, etc. Interestingly, there is a prospective study I ran across that I'm particularly interested in that is currently enrolling. For now, it's a cautionary situation. We can certainly live without grapefruit juice until we can learn more. I appreciate your suggestion but a blog is usually an opinion piece.......thanks for your post. Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 22 of 25	December 13, 2012 12:13 (EST)
	Don Kelsey	Add amlodipine to the list See And drug combinations with it. I don't think many doctors appreciate the importance of enzyme biochemistry. For example, if you have a patient on Lipitor and amlodipine and they add Prilosec and grapefruit, then you have a reall mess and no idea of real dosages they are getting. Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 23 of 25	December 13, 2012 12:17 (EST)
	Don Kelsey	URL For some reason, the URL address didn't show up in my note. Trying again.: See www.drugbank.ca for interactions of amlodipine Author's disclosure (Dec 7, 2012) I have no relevant disclosures to make in connection with this topic.
	# 24 of 25	December 13, 2012 01:36 (EST)
	Daniel Weiss	doses Don Kelsey, I think the key is that in most cases we titrate to biologic effect. We do this with warfarin.We do not tell people do not eat salads because they have vitamin K; we say keep your salad intake stable so that we can have INRs while on warfarin.I think most of this concern with grapefruit is clinically not significant. Author's disclosure (Dec 12, 2012) I have no relevant disclosures to make in connection with this topic.
	# 25 of 25	December 19, 2012 01:19 (EST)
	C.F. Ward	Cost savings Thoughtful patients, aware of this, will get a pill cutter, then take a guess at halves or quarters of the prescribed medicine,& decrease their out of pocket costs Author's disclosure (Dec 19, 2012) I have no relevant disclosures to make in connection with this topic.

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