FWD 2 The Safe Grapefruit?

HerbalEGram: Volume 10, Number 4, April 2013

The Safe Grapefruit?

Researchers develop hybrid grapefruit that does not interact with enzyme vital to medication breakdown

In March 2013, University of Florida researchers announced the development of a new and potentially “medically safer” hybrid grapefruit (Citrus paradisi), which reportedly does not interfere with the breakdown of certain pharmaceutical medications.1 The well documented “grapefruit effect” can occur when a person consumes grapefruit or grapefruit juice within hours of ingesting certain pharmaceuticals, leading to potentially life-threatening side effects. Although still in its infancy, research on the new fruit — named UF914 — could allow people taking such medications to enjoy grapefruit again without fear of drug interactions, possibly by the end of this decade.

“I believe this is an important development for those on susceptible medications who would like to consume grapefruit or its juice,” said drug interaction expert and ABC Advisory Board member Francis Brinker, ND, author of the 2010 book, Herbal Contraindications and Drug Interactions, 4th edition (Eclectic Medical Publications). “I would presume that the new hybrid grapefruit and its juice will be clearly marketed for those on medications” (email, March 25-27, 2013).

According to research by David Bailey, PhD, of the Lawson Health Research Institute in Ontario, Canada, the number of drugs with the potential for serious adverse effects associated with co-ingestion of grapefruit and/or grapefruit juice has increased in recent years from 17 in 2008 to 43 in 2012.2 The full list of medications — totaling more than 85 drugs — was published in the March issue of the
Canadian Medical Association Journal.3 Such drugs have grapefruit-interaction risks ranging from very low to very high.

In the article, Dr. Bailey — whose research group discovered the so-called grapefruit effect in the late 1980s — noted that people aged 45 and older are the primary purchasers of grapefruit and also tend to take more medications than younger individuals, making them particularly vulnerable to potentially dangerous interactions.

The Grapefruit Effect

Grapefruits contain a group of chemical compounds known as furanocoumarins, which are thought to be responsible for the grapefruit effect. Furanocoumarins affect an enzyme in the body that breaks down medications as part of the normal drug metabolism process.

“There’s an enzyme that metabolizes medicine; it takes the molecule and breaks it down into smaller pieces,” explained University of Florida researcher Fred Gmitter, PhD, the scientist responsible for developing UF914 (oral communication, March 22, 2013). “What grapefruit does is that it suppresses the activity of this enzyme. So, the enzyme isn’t working as well as it should, and therefore the concentration of the medicine in the bloodstream is elevated.”

Consequently, the level of the drug is higher than what the pharmaceutical company has found to be a reasonably safe range. Such ranges are determined as a result of pharmacokinetic tests during pharmaceutical drug testing required for drug approval, where blood serum levels are monitored for safety and efficacy. In other words, drug makers expect the body’s enzyme system to produce a predictable drug level in the blood, but if the furanocoumarins in grapefruit inhibit the enzyme, the drug level can rise above what is considered safe.

According to Dr. Bailey’s research, the metabolizing enzyme is known as cytochrome P450 3A4, or CYP3A4, which is located in cells lining the small intestine and in certain liver cells. Therefore, only orally administered medications — the majority of prescribed pharmaceuticals4 — are affected by the enzyme.

“By blocking the action of CYP3A4, these drugs are absorbed in higher levels that can lead to symptoms of drug toxicity, producing an effect equivalent to an overdose,” said Brinker. “Most drugs are metabolized primarily or in part by CYP3A4, so there are a wide variety of different types of medications that are impacted.”

Importantly, furanocoumarins are “innate to grapefruit,” and are present in all forms of the fruit: freshly squeezed juice, frozen concentrate, and whole fruit.2 The medications that are affected include many commonly prescribed drugs, from cholesterol-lowering drugs to anti-cancer agents. Researchers estimate that CYP3A4 is associated with the inactivation of roughly 50 percent of all drugs.5

According to Brinker, medications that have been reported to be affected by
grapefruit juice consumption include macrolide antibiotics (e.g., clarithromycin), immune modulators (e.g., cyclosporine), anti-arrhythmics (e.g., quinidine), HIV antivirals (e.g., saquinavir), calcium channel blockers (e.g., nifedipine), opioids (e.g., methadone), prokinetics (e.g., cisapride), benzodiazepines (e.g., midazolam), anti-malarials (e.g., halofantrine), steroids (e.g., ethinylestradiol), statins (e.g., simvastatin), and anti-histamines (e.g., terfenadine), among many others.

“When the metabolism of one drug in a category is inhibited — or induced, as in the case of St. John's wort [Hypericum perforatum], i.e., producing an opposite effect, thereby lowering drug levels in the serum — by an agent like grapefruit juice, often other drugs in that category will be similarly affected,” explained Brinker. “Typically, problems have occurred with the consumption of 200-250 ml of grapefruit juice (roughly 7-8 oz.) or more, though also with as little as 150 ml of juice (5 oz.), when taken concurrently with oral dosing of certain medications.”

Although possible side effects can range from moderate to severe, Brinker gave one example of the seriousness of the pharmacokinetics of grapefruit juice consumption. “The most extreme case of a possible interaction occurred in a man after taking the antihistamine terfenadine twice daily for more than a year,” he said. “Consumption of two glasses of grapefruit juice on a day that he was mowing the lawn led to fatal arrhythmias associated with a high plasma level of the drug.”

UF914 – The “Medically Safer” Grapefruit

As is the case with many notable scientific achievements, Dr. Gmitter discovered the fortunate chemistry of UF914 by accident while developing grapefruit-pummelo hybrids.

We started this project not looking at furanocoumarins at all,” said Dr. Gmitter. “I was making some [hybrid] crosses just to develop more deeply red-colored pummelo varieties and taking advantage of some very dark red grapefruit that we had. One of the hybrids that we selected is this one called UF914. It was first selected because it looked an awful lot like a grapefruit, just bigger. It’s got nice red blush on the outside, nice red flesh on the inside; it’s completely seedless, it has higher sugars, slightly lower acids, and is a little bit less bitter. So it’s a grapefruit that people who don’t even like grapefruit enjoy.”

While Dr. Gmitter was working on breeding, a colleague in the Florida Department of Citrus who measures furanocoumarin levels in grapefruits from around the world asked him if he had any hybrids to analyze.

“Much to my surprise, and I think to his as well, we found that some of the pummelos we were using for breeding had extremely low levels of these chemicals. But more surprising, was when we looked at some of the hybrids, we found that about 50 percent of them had very, very low levels of these chemicals and the other 50 percent were higher, like normal grapefruits,” said Dr. Gmitter. “So the UF914, luckily for us, is one that has extremely low levels of the furanocoumarin chemicals.”

Knowing that furanocoumarin levels were associated with certain drug interactions — especially in the older population that comprises much of Florida’s demographic2 — Dr. Gmitter was immediately intrigued by his colleague’s finding.

“I was thinking two things,” said Dr. Gmitter. “First of all, I am a research scientist, so I was thinking this is very interesting, why is this happening, what is the genetic control of this characteristic?”

Upon further examination of the fruits, Dr. Gmitter found that the trait responsible for the furanocoumarin levels was segregating in essentially a one-to-one fashion, indicative of a simple genetic control of the characteristic. The simple genetics behind UF914 could aid in its development as a commercially available safe grapefruit.

“Aside from being a research scientist, I am also a plant breeder and my charge is to develop new varieties that are of value to the Florida citrus industry and of value to the human population as a whole,” he added. “So this was pretty interesting, and especially since this one variety we were thinking to release anyway happened to fall into this group that has very, very low levels of furanocoumarins. So yeah, I started thinking about the commercial potential pretty quickly.”

Dr. Gmitter collaborated with a medical researcher at Tufts University who used human liver cell cultures to measure effects on the enzyme caused by the juice of UF914, ordinary graprefruit, and several other hybrids.

“We found that the juice from UF914 has virtually no effect at all on the enzyme’s activity,” said Dr. Gmitter. “Whereas ordinary grapefruit or those other hybrids that have the higher furanocoumarins, they suppress the activity of that enzyme in vitro. So that’s another clue to us that potentially, possibly, this grapefruit hybrid is something that might be safe for people who are taking all these various medications.”

Future research

Before UF914 can be marketed as a safe grapefruit, scientists will need to conduct human clinical trials to measure the effects in individuals taking medications known to interact with the fruit. Dr. Gmitter noted that this next stage is substantially more expensive than the research that has already been conducted, although such logistical discussions are already underway.

“[UF914 has] actually been approved for release,” he said. “And right now there are some discussions taking place between the University, which will have a patent on this variety, and the Florida citrus industry. Somebody will be taking this variety and growing it regardless of whether we’re going to make any claims on it or not. Theoretically, we could just release this thing and say, ‘Here is a new larger, better tasting grapefruit,’ and not say anything at all about the furanocuourmarins.”

Without making any specific health claims, researchers would be able to release the variety for sale in grocery stores around the country. However, for UF914 to be sold as a safe grapefruit, the US Food and Drug Administration will require more research.

“My most optimistic estimate is that it’s going to be five years from now before this fruit is on the market,” said Dr. Gmitter. “While all that is taking place, if there’s a major beverage company that wants to commercialize this thing and promote it and advertise it, they might be the guys who go ahead and do human clinical trials.”

Interestingly, Dr. Gmitter and his colleagues in the Food Resource and Economics Department of the University of Florida already have conducted focus groups with the new fruit. Participants were divided into two groups — those who buy citrus fruit and who like grapefruit and those who buy citrus fruit but do not like grapefruit — and then presented UF914 to both groups.

“The people who liked grapefruit thought this was a really good grapefruit. The people who didn’t like grapefruit actually liked this hybrid as well, and I think that’s probably a consequence of it being sweeter tasting,” said Dr. Gmitter. “And then the concept of it being medically safer was introduced, and that was something that went over really [well].”

Although UF914 is larger and redder than ordinary grapefruits, the focus group participants said that they appreciated its slightly different appearance, something that could help them distinguish “safe” grapefruits from “unsafe” grapefruits in the marketplace.

“One or two people asked, ‘Is this a GMO?’ and the answer is no, it’s not,” said Dr. Gmitter. “It’s developed by the old-fashioned way — taking pollen from one parent and putting it on the flower of another and collecting the seeds and growing them and selecting the best ones.”

Although it may be a number of years before UF914 can be marketed and sold as a safe grapefruit, Dr. Brinker added that not everyone needs to be concerned about their current grapefruit eating habits.

It is important to keep in mind that it is not the grapefruit that is unsafe, but it is the medications for which metabolism is reduced by grapefruit furanocoumarins that become increasingly unsafe when the two are used together,” Brinker explained. “For those who are not consuming potentially toxic medications, consumption of grapefruit is a cause for enjoyment and not for concern.”

—Tyler Smith


1.       Liston B. Florida researchers develop medically safer hybrid grapefruit. Reuters. Available here. Accessed March 22, 2013.

2.       Bailey DG, Dresser G, Arnold M. Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? Canadian Medical Association Journal. 2013;185(4):309-316. Available here. Accessed March 26, 2013.

3.       Appendix 1: Grapefruit Interacting Drugs and Associated Oral Bioavailability, Adverse Event(s), Risk Ranking and Potential Alternative Medications. Bailey DG, Dresser G, Arnold M. Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? Canadian Medical Association Journal. 2013;185(4):309-316. Available here. Accessed March 26, 2013.

4.      Drug administration. The Merck Manual website. Available here. Accessed March 29, 2013.

5.       Wilkinson GR. Drug metabolism and variability among patients in drug response. New England Journal of Medicine. 2005;352:2211-2221. Available here. Accessed April 1, 2013.