i-c7c16e11a8558c90b1fa7671f180b804-government_issue_grapefruit_photograph.jpg

photograph of some grapefruit
Grapefruit juice contains enzymes that break down common types of compounds of which pharmaceuticals are made. This means that if you drink grapefruit juice along with some drugs, the effect of the drug will be enhanced.

(That was a slight oversimplification.)

So great, you say, why not just take all drugs with a glass of grapefruit juice? Well, I can think of two reasons. One, grapefruit juice tastes like ape-piss, so why would you ever drink it. Two, drug experts feel that they have more control over your dosage if you just leave the grapefruit juice out of the equation.

But, not always.

New findings from a University of Chicago research team suggest ways in which grapefruit juice can play a useful role. From a UC press release:

In a small, early clinical trial, researchers at the University of Chicago Medical Center have found that combining eight ounces of grapefruit juice with the drug rapamycin can increase drug levels, allowing lower doses of the drug to be given. They also showed that the combination can be effective in treating various types of cancer.

For two decades, pharmacists have pasted do-not-take-with-grapefruit-juice stickers on various pill bottles because it can interfere with the enzymes that break down and eliminate certain drugs. This interference makes the drugs more potent. In data presented at the AACR 100th Annual Meeting 2009, the Chicago researchers examine ways to exploit this fruit’s medication-altering properties.

“Grapefruit juice can increase blood levels of certain drugs three to five times,” said study director Ezra Cohen, MD, a cancer specialist at the University of Chicago Medical Center. “This has always been considered a hazard. We wanted to see if, and how much, it could amplify the availability, and perhaps the efficacy of rapamycin, a drug with promise for cancer treatment.”

This trial was designed to test “whether we could use this to boost rapamycin’s bioavailability to the patient’s advantage, to determine how much the juice altered drug levels, and to assess its impact on anti-cancer activity and side effects,” he said.

The study followed 28 patients with advanced solid tumors, for which there is no effective treatment. The dose of the drug increased with each group of five patients, from 15 milligrams up to 35. Patients took the drug by mouth, as a liquid, once a week.

Beginning in week two, they washed it down with a glass of grapefruit juice (Citius paradisi), taken immediately after the rapamycin and then once a day for the rest of the week.

Twenty-five participants remained in the study long enough to be evaluated. Seven of those 25 (28 percent) had stable disease, with little or no tumor growth. One patient (4 percent) had a partial response, with the tumor shrinking by about 30 percent. That patient is still doing well more than a year after beginning the trial.

“My first cancer doctor gave me five years to live,” said that patient, Albina Duggan of Bourbonnais, IL. “That time runs out next July.”

Duggan, mother of four, has a rare cancer, an epitheliod hemangioendothelioma that originated in the liver and subsequently spread to two vertebrae in the neck and to the lymph nodes. She had surgery and radiation therapy and was evaluated for a liver transplant, but evidence of cancer beyond the liver made her ineligible for a transplant. She “shopped around” for other therapies and was able to keep the disease in check for a year with sorafenib, a drug approved for kidney and liver cancers.

After a year of stable disease, however, her tumor began growing again and she had to look for an alternative therapy. Her doctors at the University of Chicago offered three clinical trials. The most appealing to her was the rapamycin plus grapefruit juice study. She took her first dose March 11, 2008, and is still on the drug-juice combination.

“My tumor is smaller and it’s no longer growing. I feel fine. I can do whatever I like and I have no real side effects,” she said. “What’s not to like?”

Trial subjects do not like the taste of rapamycin. “It’s not pleasant,” Duggan admitted. She has also tired of grapefruit juice.

Many patients in the study did report side effects. More than half experienced elevated blood sugar levels, diarrhea, low white blood cell counts or fatigue.

Duggan, more fortunate than most, has had milder side effects, including fragile toe and finger nails and curly hair. “I now have very curly hair,” she said, “seriously curly. I have to adjust to it.”

Rapamycin, also known as sirolimus, was originally developed to suppress the immune system, preventing rejection in patients receiving a transplanted kidney. Cancer specialists became interested in the drug when they learned that it disrupted a biochemical pathway involved in the development of the new blood vessels that tumors need to grow. But the drug is expensive and poorly absorbed. Less than 15 percent of rapamycin is absorbed when taken by mouth.

This study showed that substances known a furanocoumarins, plentiful in some forms of grapefruit juice, can decrease the breakdown of rapamycin. This makes the drug reach higher levels in the bloodstream, two to four times the levels seen without a juice boost, and thus increases the amount of the drug that reaches its targets.

“That means more of the drug hits the target, so we need less of the drug,” said Cohen.

Many of the newer cancer medications, precisely focused on specific targets, are now taken as pills rather than intravenously. Some of these drugs, including rapamycin, can cost thousands of dollars a month. Hence, “this is an opportunity for real savings,” Cohen said. “A daily glass of juice could lower the cost by 50 percent.”

Comments

  1. #1 CybrgnX
    April 29, 2009

    Interesting post. But I have a question….
    When did you ever drink ape piss so you would know what grapefuit juice tastes like???? And how did you convince it to pee in the like bottle???

  2. #2 Nathan Myers
    April 29, 2009

    It’s clear why pharma is motivated not to investigate the option of recommending grapefruit juice with drugs; it decreases sales of all but the most expensive. I wonder whether including the grapefruit enzymes in the pills would actually reduce variability in the absorption and elimination rates.

  3. #3 Jason Thibeault
    April 29, 2009

    I love that you helpfully labelled the picture so we might not mistake it for a bottle of ape piss. So thoughtful.

    I’d like to know why everyone immediately suspects Big Pharma of dirty dealings when some heretofore unknown fact about a natural product or remedy turns out to combat disease, or enhance existing treatments. Just because they didn’t hit upon the possibility themselves doesn’t mean that cancer-drug producers knew about grapefruits’ enzymes’ effects on their drugs to begin with. Without any evidence of wrongdoing, I wouldn’t jump to the conclusion that they’re being evil. Think horses, not zebras… at least until you see stripes.

  4. #4 NewEnglandBob
    April 29, 2009

    I enjoy grapefruit juice and I had a glass of it with dinner tonight. It goes well with Moussaka. I guess I need to try ape piss, since Greg has already tried it in a comparison.

    Actually, being a heart patient, there was one drug I was taking that specifically said that grapefruit and its juice should be avoided. I don’t recall which drug that was. I remember the write up saying that grapefruit negated the drug. My cardiologist said to avoid the combination for 2-3 hours.

  5. #5 Jadehawk
    April 29, 2009

    pffft. grapefruit juice is tasty.

    now tomato juice on the other hand….

  6. #6 David
    April 29, 2009

    I work for a pharma company, but not one that makes chemotherapy.

    Cytochrome 3A4 is a notorious pain-in-the-a.., especially for drugs with serious toxicities, and hence, a narrow therapeutic index. Most chemo drugs are dosed within very narrow limits, and getting the dose right is the difference between life and death. There is huge population variability in the level of activity of Cyp3A4, but there is also huge variability in the responsiveness to 3A4 inhibitors. Grapefruit juice in general is a good inhibitor of gut cytochrome, not so much hepatic cytochrome. So the effect depends on the amount of grapefruit juice in the gut at the time the chemo drug is being absorbed. Consider that the level of grapefruit juice in the gut would go up and down during the course of the day, effected by variables like diet and activity, so the clearance rate of the chemo drug would become highly variable hour-by-hour. This is a nightmare. I can see how they can get impressive results in the setting of a phase 1 drug study, where all the variables are controlled. But in real life this is strikes me as a really really high-risk idea. For “really high-risk” you can substitute “stupid” (keep one of the reallys).

    Nathan, hate to burst your pharma-bashing bubble, but if drug companies could get the same effect out of a lower dose, they would be lowering their cost-of-goods. If I had a cheap way of putting out pills that were equally effective at lower costs, my profit would go up.

    Drugs aren’t priced by how much they cost to manufacture – that’s usually cheap, as proven by generics. Drugs are priced by the immense R&D costs, and by the putative savings they produce (either in improved health or reductions in other kinds of care).

  7. #7 Greg Laden
    April 29, 2009

    That is an un-copyrighted US government photograph of grapefruit. I labeled it with the purely mercenary hope that it would get picked up by Google Image for anyone searching for grapefruit pictures, who would then discover my blog. Like the chicken picture.

    Ape piss is an Africanist archaeologist expression. Someday I’ll tell everyone the ape piss story.

  8. #8 Benjamin Geiger
    April 29, 2009

    I absolutely abhor grapefruit juice, and my body tends to agree (it gives me canker sores). But, if it’s to save thousands of dollars per month, I’d put up with some daily nastiness. In any case, it tastes infinitely better than MoviPrep.

    What are the odds that someone will research and sell the enzymes in question in pill/gelcap form?

  9. #9 samantha
    April 29, 2009

    I have several medications that say to avoid grapefruit juice (halcion, fentanyl).
    For the life of me, I’ve never understood why we’re paying through the ass for ritanovir to boost other protease inhibitors by inhibiting CYP450 3A4 when 3A4 inhibitors have to be a dime a dozen. I like the ruby red + would greatly prefer to drink that than take a dinosour-sized Norvir twice a day.

  10. #10 Kamel
    April 29, 2009

    Greg, I’ve forwarded this post to the host for this month’s Cancer Research Blog Carnival (http://cancer-carnival.blogspot.com) that will be appearing on Friday. Hope you don’t mind.

  11. #11 Nathan Myers
    April 30, 2009

    David: Thank you for the education. Should we assume that the trials with grapefruit juice really are preliminary to putting the appropriate enzymes in the pill?

  12. #12 David
    April 30, 2009

    Nathan, I have no particular knowledge of why the authors of the cited study did what they did. I think adding intestinal CYP inhibitors to a drug regimen is probably a bad idea, potentially leading to erratic and unpredictable changes in pharmacokinetics. I’m currently working on several drug programs involving CYP 3A4, and I generally require trial participants to avoid potent inhibitors. It just seems safer that way.

    That said, there have been some serious attempts at this approach, see Thisted et al Clin Ther 2006

  13. #13 llewelly
    April 30, 2009

    And how did you convince it to pee in the like bottle???

    If an ape thinks you’ll be drinking out of the bottle, he’ll be more than happy to pee in it. Whether you want him to or not.

  14. #14 Argon
    April 30, 2009

    Grapefruit juice contains enzymes that break down common types of compounds of which pharmaceuticals are made. This means that if you drink grapefruit juice along with some drugs, the effect of the drug will be enhanced.

    ???!!! It might be good to fix that info.

  15. #15 paula
    April 1, 2011

    I found sucking a wedge of cold grapefruit was a brilliant cause for nausea while on chemo (FEC100 and Taxotere/ Docetaxel. It stopped me feeling yeuky literally seconds after ingesting it. My mum gave me this tip as it worked for her when she had chemo in the 1970s.(I know there are some chemo combinations + clinical trials of new anti-cancer drugs where is it not advised.)

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