MPIP: Melanoma Patients Information Page

The MPIP is the oldest and largest community of people affected by melanoma hosted through the Melanoma Research Foundation. It is designed to provide support and information to caregivers, patients, family and friends. Once you have been touched by melanoma—either as a patient or as a family member or friend of a patient—you become part of a community. It is not a community anyone joins willingly. But if you must be part of this group, you will find no better place to find the tools you need in your journey with this cancer, and the friends who can make that journey more bearable.

The information on the bulletin board is open and accessible to everyone. To add a new topic or to post a reply, you must be a registered user. Please note that you will be able to post both topics and replies anonymously even though you are logged in. All posts must abide by MRF posting policies.

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Mat's picture
Replies 22
Last reply 5/26/2014 - 9:43pm
Replies by: Leonardostagg, Mat, GAngel, tico1, Anonymous, Janner, G-Samsa, BrianP, Phil S, POW

Hi Everyone,

First, I want to express my gratitude and appreciation for the folks who post to this bulletin board.  I've learned so much in a short period of time from your posts.  As you know, as is often the case in life--but especially with melanoma--ignorance is not bliss.  As a result of your posts, I've felt more comfortable discussing treatment options, etc. with my doctors, family and friends.  Thank you.

As for my story, in 2003, I was 29 years old.  I had a small mole on the far right side of my chest near the right arm socket.  For the past year (probably more), it was taking on an odd shape, discoloration.  In hindsight, with the benefit of Google pictures, etc., a clear case of melanoma.  After much nagging over a period of many months (maybe more) from my parents and then girlfriend (now wife), I had the mole removed in a dermatologist's office.  (One of the reasons I had delayed (aside from youthful foolishness) is that a general practitioner had looked at the mole and said it looked "fine"--a lesson that this is not an area for general practitioners (no offense to any readers).)  A few days later, I received "the call".  The dermatologist referred me to one of the top melanoma specialists in my city (Philadelphia).  I proceeded to have a wide incision, sentinel lymph node testing, PET scan.  All were clear.  My melanoma was considered "thin" at .50mm, level 2.

For the next 9 years, I continued to see my oncologist.  The appointments were every 6 months until 2011 when I was switched to annual appointments.  I was scanned for 3 years and then we switched to chest X-rays (all of course with blood work).  The running joke with my oncologist was that I was just there to pay him my co-pay and say hello.  Melanoma was a distant memory.  I was very foolish by not being more vigilant with the mole, but I got lucky and had dodged a bullet . . . or so I had thought.

Of course, 2013 would turn out to be quite different.  I went to my routine annual appointment at the end of June with essentially only one symptom--around April, I started to develop what I thought was an under the skin-cyst on the top of my right shoulder.  My wife was 8 mos. pregnant.  We were busy.  I'm not sure that melanoma even crossed my mind.  I went to my primary care physician (different from the one mentioned above, but the same lesson still applies)--he thought it was a cyst from an in-grown hair.  However, it was on my "shoulder-bag" shoulder and was bothering me, so I went to the dermatologist--she thought it was a lipoma (a harmless fatty mass).  Even my oncologist thought it was a cyst or lipoma.  (Of course, the "cyst" would turn out to be melanoma--more on that below.)  Aside from the "cyst", two new developments at my oncologist appointment--for the first time in 10 years, I had an elevated LDH level (330) and a "spot" in my lungs on my chest X-ray.  My oncologist told me that it was "almost statistically impossible" for this to be a recurrence of melanoma.  We re-did the bloodwork to confirm--LDH level still elevated.  We did a CT scan--total disaster.  Stage IV metastasized melanoma all over the place--liver, abdomen, lungs, bone lesions, more.  

Before I move on, let me pause.  The reason I'm including this level of detail is not because I'm looking for sympathy.  I know that some readers who visit this board are Stage I, consider themselves lucky, etc.  Well, that was me (except I didn't bother visiting the board)!  You cannot be too vigilant about this disease.  In hindsight, I'm not sure what I could have done differently (aside from getting the mole removed earlier)--insisted on a periodic CT scan whether or not covered by insurance?  I don't know.  I recognize that my situation is somewhat unique in that the vast majority of Stage I patients who are clear for 10 years remain so--but there is a statistically significant portion of those folks who have a recurrence.  Be vigilant--and see the "top" melanoma specialist (not "one of the top") in your area.

Back to my story, which resumes on July 10th.  My oncologist's "plan A" was to have me screened by the NIH for one of their protocols.  I researched the TIL treatment online (thank you Bob Heffernan for your posts and your book (a great read which is available on Amazon!)).  I liked the plan, though I did switch my care over to Dr. Lynn Schuchter at UPenn (the "top" melanoma specialist in the Philadelphia-area).  Of course, it took a few weeks to get through the NIH's process.  I received "the call"--I was eligible, subject to being re-scanned at NIH.  The re-scans were a total disaster--significant tumor progression, particularly in my liver.  One small brain met.  I probably couldn't live long enough to go through the TIL process (which takes a number of weeks).  Whereas just a week or so prior, I was reviewing the "menu" of options (ipi/PD-1 trials, etc.), I now had almost none.  Fortunately, UPenn had tested me for the BRAF mutation and I tested positive for BRAF-V600E.  All of the doctors (UPenn and NIH) agreed that I needed to move immediately to a BRAF inhibitor.  (I should also mentioned that within this time frame my blood was re-tested--LDH now at 600 and most liver functions were elevated.)

Dr. Schuchter prescribed the Tafinlar-Mekinist combo (and my insurance company cooperated!).  Last Friday evening--just 8 days ago--I started on the combo.  Within 2 days, the tumor on my shoulder started to decrease in size.  By the end of the week, it was a small fraction of the size it was just a week ago.  My only other surface-level tumor--a small nodule on my left arm--totally disappeared.  Recently, I had developed liver pain/sensation.  Throughout the week, this seemed to be improving--by the end of the week, I was certain that it was improving (easier to move around in bed, pull on a heavy door, etc.).  By the end of the week, I also "felt better", had more energy, was able to work a full day without fatigue, etc.  Yesterday--just 7 days after starting treatment--I had my blood re-tested.  All liver functions are essentially normal, with LDH being only slightly elevated at 240.  In my case, so far, these are miracle drugs.  I recognize that the treatment is a "bridge treatment" and will not last, but I need a "reset" badly--and these drugs appear to be providing one.  Of course, I won't know for certain until I'm re-scanned in a few weeks.

As for side effects, I'm early in the cycle, but so far, I'm only getting joint pain (particularly in the hips).  However, this is totally manageable and a small price to pay.  For any Stage IV patient reading this--if you are BRAF-V600E positive and your tumor progression is such that other options aren't presently available, this combo seems to be a great option.  Thank you Dr. Schuchter (and her entire staff), thank you GlaxoSmithKline for developing these drugs, and thank you to all of the melanoma patients who participated in the trials for these drugs!

Please feel free to ask questions and I will do my best to respond promptly.

Very truly yours,


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Replies by: JerryfromFauq, POW


Curcumin (CUR), a naturally occurring polyphenol derived from the root of Curcuma longa, has showed potent anticancer and cancer prevention activity in a variety of cancers. However, the clinical translation of CUR has been significantly hampered due to its extensive degradation, suboptimal pharmacokinetics, and poor bioavailability. To address these clinically relevant issues, we have developed a novel CUR-loaded magnetic nanoparticle (MNP-CUR) formulation. Herein, we have evaluated the in vitro and in vivo therapeutic efficacy of this novel MNP-CUR formulation in pancreatic cancer. Human pancreatic cancer cells (HPAF-II and Panc-1) exhibited efficient internalization of the MNP-CUR formulation in a dose-dependent manner. As a result, the MNP-CUR formulation effectively inhibited growth of HPAF-II and Panc-1 cells in cell proliferation and colony formation assays. The MNP-CUR formulation suppressed pancreatic tumor growth in an HPAF-II xenograft mouse model and improved the survival of mice by delaying tumor growth. The growth-inhibitory effect of MNP-CUR formulation correlated with the suppression of proliferating cell nuclear antigen (PCNA), B-cell lymphoma-extra large (Bcl-xL), induced myeloid leukemia cell differentiation protein (Mcl-1), cell surface–associated Mucin 1 (MUC1), collagen I, and enhanced membrane β-catenin expression. MNP-CUR formulation did not show any sign of hemotoxicity and was stable after incubation with human serum proteins. In addition, the MNP-CUR formulation improved serum bioavailability of CUR in mice up to 2.5-fold as compared with free CUR. Biodistribution studies show that a significant amount of MNP-CUR formulation was able to reach the pancreatic xenograft tumor(s), which suggests its clinical translational potential. In conclusion, this study suggests that our novel MNP-CUR formulation can be valuable for the treatment of pancreatic cancer. Mol Cancer Ther; 12(8); 1471–80. ©2013 AACR.


I'm me, not a statistic. Praying to not be one for years yet.

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Replies by: Anonymous, ClaudeM, BrianP, chalknpens, blden2186, Johnfdc7

I have completed the 4 weeks of IV interferon, radiation of right leg, and am starting the self injections in a week. Does anyone have any advise as to the best time of day to administer? I want and need to work so I hope to minimize side effects.

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Replies by: JerryfromFauq, wpneuma

I have completed the 4 weeks of IV interferon, radiation of right leg, and am starting the self injections in a week. Does anyone have any advise as to the best time of day to administer? I want and need to work so I hope to minimize side effects.

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Violet's picture
Replies 4
Last reply 1/2/2017 - 5:21am

My sister was diagnosed with metastatic melanoma in April 2012 . She had a limphnode surgery in her left arm. Over summer melanoma came back. and meanwhile doctors found another metastasis in her hip. She experienced four months of the most awful pains I have ever sow and she was close to die. In September 2012. Zelboraf saved her and gave her another valuable 10 months. She went back to the university where she is teaching and had almost a normal life again.

Now, the zelboraf is not working anymore. The tumor from her arm is growing fast and her oncologist recommended Yervoy and radiotherapy. We are again in a bad situation, because the insurance provider is not covering these expensive treatments in Romania. Her previous treatment with zelboraf was possible due the humanitarian campaign organized by her colleagues at University of Bucharest. Although the campaign continues, we do not have big hopes that this time it will bring enough funds to cover her treatment with Yervoy.

I spent some time looking for charity organizations and foundations that are financially assisting patients with cancer, but I found nothing for Europe.Do you know any Financial Assistance Program in Europe or any Charity Foundation granting patients in Europe too? What I have found on internet is granting patients in USA , but I did not find anything similar for Europe. If they are also active in Europe, I would like to write them and to apply for funds if she is elligible. I sow that Bristol Myers has a financial assistance program but not running in Europe, and for sure not in Romania..

Here is the fundraising campaign for my sister, please have a look : ....//  Please share the link with anybody you think is in the position to help us or to gave us a good idea about how we can access the treatment with Yervoy for my sister. Any advise is welcome!


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Pink's picture
Replies 5
Last reply 8/31/2013 - 5:39pm
Replies by: Tina D, Pink, BrianP, casagrayson

After 6 years I have mets in my leg. I just had a Pet and brain MRI which were negative. I am seeing Dr. Zager at Moffitt on Monday to see my optinns. What treatments recommended at this point

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Replies by: Tina D, GAngel

Haven't updated in awhile, but we are back in TX and had my appointment with Dr. Papa this morning. Scans looked good. The spot on my liver is responding well. Smaller with less uptake on the PET.  I have been having issues with diarrhea for a few weeks now. Went to TX 6/13 and  he added Yervoy. I was already having some diarrhea then I assumed from the Zelboraf. Had Yervoy 7/3/13. Put in hospital 7/26/13 for increased diarrhea. turned out to be cdiff. Cleared all that up, but diarrhea still persists. Been on steriods since 8/1/13.  This trip he also decided not to continue Yervoy due to this.  Will have a colonoscopy to make sure it is not colitis. If not colitis, I can stop the steriods. Overall I feel blessed and optimistic that all is going well.



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Sherron's picture
Replies 13
Last reply 8/12/2013 - 1:53pm

Baby Addison Cox of Phoenix passsed away last night of Stage 4 Melanoma.  She was born with Stage 4, passing through the placenta.  Her mother has already passed away, and I read last night that Addison passed away in the arms of her Daddy....she and her mother are together once again...You can goggle it and look up the story...So very sad. I do not know if they were a member of the MPIP family or not.

Take Care,

Sherron, wife to Jim FOREVER AND ALWAYS

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Sherron's picture
Replies 1
Last reply 8/9/2013 - 4:12pm
Replies by: Tina D

Baby Addison Cox of Phoenix passsed away last night of Stage 4 Melanoma.  She was born with Stage 4, passing through the placenta.  Her mother has already passed away, and I read last night that Addison passed away in the arms of her Daddy....she and her mother are together once again...You can goggle it and look up the story...So very sad. I do not know if they were a member of the MPIP family or not.

Take Care,

Sherron, wife to Jim FOREVER AND ALWAYS

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saraheh's picture
Replies 6
Last reply 8/9/2013 - 2:05pm
Replies by: Anonymous, POW, jeffjohn78

I was just diagnosed this week with possible Stage 1a melanoma.  It might be in situ, but they could not rule out invasion due to nests and a bunch of inflammatory cells.  Whatever that means, I have no idea.  I have a surgery scheduled next week to remove surrounding tissue from the site and then they say that I will have skin checks at 3 months.  I cannot help but think that there is something else that I should be doing or looking into.  They mentioned an eye exam, which I will do.  I also plan to see my naturopathic doctor to help make sure my immune system is in top shape and any deficiencies in nutrients can be corrected.  I just do not want this to come back.  I am thankful it is still early, but I also have a 6, 4, and a 2 year old that I want to stay healthy for.  

Anything else that I should be doing or requesting at this point?  I do not want to always be worrying that this cancer is heading somewhere in my body to rear its ugly head in a few years.  The doctors seem to think that getting this cut out will solve it and I will not have future problems.  Should I get a second opinion on the lab results?

Please help!

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Replies by: Tina D, Jim M., Anonymous


Hi all, I hope everyone is doing well and in good spirits.

Quick question to everyone as my web searches have been fruitless and I've pestered my doctors to no end....

A quick refresher: Stage 1a melanoma (.82mm, no mitosis, no ulceration, Clark IV). Had SLNB on right groin with three nodes given the all clear. This occurred in early Feb. 13.

Now, the question: Since mid April both of my armpits have had a constant ache. Not a pain, just an ache. The best way to describe it is to think of holding a tennis ball under your arms. I've been to my derm and my oncologist, both of which said it isn't anything. I had an ultrasound that looked fine as well. There is nothing palpable, etc.

Has anyone else experienced this? Could this be a result of my WLE and my fluid being rerouted? I've never been one to worry about illness, but since my dx, I've become a hypochondriac. Should I keep pushing for more tests?

I had a CT scan in March when I visited MD Anderson and all was clear (expect for a 6mm nodule in my groin which they assume is an inflamed node from my surgery). Should I ask MD for another CT scan? A Pet CT?

Thanks for any input.


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Curious to know if anyone has had experience with this drug. I suppose we all will find out soon with phase 3 results coming soon, but I've been curious to know of any success or failure stories out there. I haven't heard much about it since I was diagnosed 6 years ago. Just trying to keep up with everything.



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Wetterhorn's picture
Replies 2
Last reply 8/9/2013 - 4:39pm
Replies by: Pink, DeniseK

6 years and 1 day ago I had my suspicious mole removed by the dermatologist. I guess I wasn't given the news for another week, so not really sure what "official" anniversary date counts, but needless to say, good to still be here. Been a rough road with 6 surgeries, countless hospitalizations, and a destroyed thryoid and adrenal glands due to an inflamed pituitary casued by yervoy, but also stable disease 2 years since yervoy with a small lesion on my liver.  Anyway, there were too many times that I did not think I would be around in 2013, but happy to still be here. For those that have been recently diagnosed or have been battling, keep up the hope.


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brooke's picture
Replies 5
Last reply 8/8/2013 - 8:48pm
Replies by: vivian, Anonymous, Janner, POW


I've seen on other posts stating that some people are staged based on mitotic index. Just wondering how good a predictor of spread it is?

My husband's path report showed <1/mm2, which I'm assuming is good? Also, Breslow depth was 1mm and no ulceration. Still categorized as IIIb due to the small satellite lesion found in the biopsy. 

Just reaching for any hope!

Thanks again!


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Replies by: chalknpens

Nutrition Journal
BioMed Central



Medicinal importance of grapefruit juice and its interaction with various drugs

Jawad Kiani and Sardar Z Imam

Additional article information



Grapefruit juice is consumed widely in today's health conscious world as a protector against cardiovascular diseases and cancers. It has however, been found to be an inhibitor of the intestinal cytochrome P – 450 3A4 system, which is responsible for the first pass metabolism of many drugs. The P – glycoprotein pump, found in the brush border of the intestinal wall which transports many of these cytochrome P – 450 3A4 substrates, has also been implicated to be inhibited by grapefruit juice. By inhibiting these enzyme systems, grapefruit juice alters the pharmacokinetics of a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on the calcium channel antagonist and the statin group of drugs. In the case of many drugs, the increased serum concentration has been found to be associated with increased frequency of dose dependent adverse effects. In this review, we have discussed the phytochemistry of grapefruit juice, the various drugs involved in the drug – grapefruit juice eraction with their mechanisms of action and have presented the clinical implications of these interactions.


The grapefruit, thought to be a cross between an orange and a shaddock, was developed in the West Indies in the early 1700s and first introduced to Florida in the 1820s. Since the early part of the 20th century, mutant strains of white grapefruit have appeared with pink to slightly reddish colour, and have been propagated by citriculturists into several strains of grapefruit. The three major types of grapefruit that exist today are white, pink/red and ruby/rio red varieties. Grapefruit juice combines the sweet and tangy flavour of the orange and shaddock and also provides up to 69% of the RDA for vitamin C along with as many as 250 mg of Potassium [1].

However, the wide consumption of grapefruit juice cannot entirely be attributed to its taste, and nutritive value. In fact, much of the enthusiasm in its use stems from medical research that has suggested that grapefruit juice reduces atherosclerotic plaque formation [2] and inhibits breast cancer cell proliferation and mammary cell tumorigenesis [3,4]. Traditionally grapefruit juice has been found to contain antioxidant, antinitrosaminic, antiseptic, aperitif, cardiotonic, detoxicant, hypocholesterolemic, sedative and stomachic activities. In the light of its above activities, it has been traditionally indicated throughout time for anorexia, bacteria, benign prostatic hypertrophy, cancers (breast, colon, prostate, lung, skin and throat), candida, cold, diabetes, dysuria, high cholesterol, infection, insomnia, mycobacterium, mycosis, nervousness, pseudomonas, rheumatism, staphylococcus and yeast.

However, as many as fifteen years ago, investigators found that grapefruit juice can markedly augment oral drug bioavailability. This was an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used as a flavour supplement to mask the taste of the ethanol [5]. Studies that followed, confirmed that grapefruit juice significantly increased the oral bioavailability of felodipine [6,7]. Subsequent studies probed the constituents of grapefruit juice, its interaction with various other drugs and the mechanisms of action of those interactions. Several grapefruit juice-drug interactions were discovered and these remain a potential concern especially since the juice and drugs are often consumed together at breakfast. An increasing number of adverse drug reactions might be avoided on the basis of knowledge about the interaction of grapefruit juice and relevant drugs. Therefore, patients need to be educated about the hazards (and advantages) of grapefruit interaction with medication. In recent years, more drugs have been investigated for their interaction with grapefruit juice and new models have been proposed for the mechanism of such interaction. This article presents a simplistic summary of most examples of such interactions and also explores the phytochemistry and possible mechanisms of action involved in drug-grapefruit juice interactions in light of recent studies on this subject.

Mechanism of action

The mechanism of action of this interaction involves inhibition of the CYP 3A4, a member of the cytochrome P 450 (CYP) enzyme system. CYP is a large multigene family of heme-containing enzymes located in the endoplasmic reticulum of cells throughout the body. It is especially concentrated in the liver and intestinal wall where it is involved in oxidative biotransformation of various endogenous and exogenous substances. CYP 3A isoforms constitute 70% of CYP enzymes in enterocytes [8,9]. P-glycoprotein (Pgp), a member of the ABC (adenosine triphosphate-binding cassette), is another membrane transporter located in the apical brush border of enterocytes. Once taken up by the enterocytes, a lipophilic drug may be metabolized by CYP 3A4 or be pumped back into the lumen by the Pgp. Hence the oral delivery of many drugs is limited by the actions of CYP 3 A4 or Pgp. Metabolism by the CYP 3A4 will also occur in the liver before the drug finally enters the systemic circulation. Grapefruit juice causes inhibition of CYP 3A4 and thus serves to increase the bioavalability of the drug by decreasing its pre-systemic metabolism [10]. This action is in essence, similar to that caused by CYP-inhibiting drugs like itraconazole, ketoconazole and erythromycin [11-13].

Grapefruit juice causes quick and irreversible sustained inhibition of the CYP system, possibly by greatly accelerating the degradation of these enzymes while also reducing translation from its mRNA. However, the process of transcription of mRNA from the cell DNA is not affected. Overall, grapefruit juice reduces the levels of CYP 3A4 in the cells by as much as 47% within four hours of ingestion of grapefruit juice with the resultant increased bioavailability being maintained for as long as 24 hours, by which time 30% of its effect is still detectable [14-17]. It has been observed that decreased content of CYP3A4 was not associated with increased CYP3A4 mRNA, probably indicating the absence of a feedback mechanism for CYP3A4 expression. Restoration of CYP3A4 activity would therefore require denovo synthesis or enterocyte replacement, accounting for the prolonged duration of the actions of grapefruit juice [18].

Grapefruit juice shows a high variability of the magnitude of effect among individuals. This variability is dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 have the highest proportional increase [19,20]. However, the effects of grapefruit juice are predominantly on the intestinal CYP rather than hepatic CYP. This is shown by the fact that most of the drugs that are involved in interaction with grapefruit juice undergo their primary metabolism at the intestinal level and in usual quantity, grapefruit juice does not affect the pharmacokinetics of these drugs when they are administered intravenously. Furthermore, while it increases the area under the plasma concentration-time curve (AUC), it has no significant effect on the half life of the drugs [10,21-23].

In contrast to the clear inhibitory effects of grapefruit juice on CYP 3A4, the effects of grapefruit juice on Pgp are controversial, ranging from activation to inhibition. Earlier results have shown grapefruit juice to cause activation of Pgp in vitro [24]. Any such activation in vivo will mean a greater efflux of the drug back into the lumen, thereby decreasing the oral bioavailability of that drug and at least partially, if not completely offsetting the effects produced by the inhibition of CYP system of enzymes. This is taken as an explanation for the less-than-expected increase in the bioavailability of drugs that are established substrates of Pgp [24]. However, grapefruit juice does not change the absorption of digoxin, a prototypical P-glycoprotein substrate, likely because it has high inherent oral bioavailability [17,25]. However, recent studies have demonstrated the inhibition of Pgp by grapefruit juice both by its down-regulation and inhibition of function [26,27]. For example, grapefruit juice increases the bioavailability of cyclosporine. This effect is thought to be primarily though Pgp inhibition (instead of CYP3A4 inhibition) since orange juice mediated reduction in enterocyte CYP3A4 concentrations did not produce a similar increase in bioavailability [17]. In fact, grapefruit juice has also shown inhibition of multidrug resistant protein 2 (MRP2), an efflux protein closely related to Pgp in terms of its expression and function [26].

Yet, in spite of all what is known, the mechanism of action of grapefruit juice-drug interaction requires further investigation. Investigators still need to determine for certainty any in vivo effect of grapefruit juice on Pgp. One study [28] has also reported the action of grapefruit juice independent of its actions on Pgp and CYP 3A4. This also requires further investigation. Similarly, grapefruit and even orange juice have also recently been shown to be potent in vitro inhibitors of a number of organic anion-transporting polypeptides (OATPs) that are involved in apical-to-basal transport of drugs in the small intestine [17,18,25,29]. They were also found to decrease the absorption of the non-metabolized OATP substrate, fexofenadine hence pointing towards inhibition of intestinal uptake transporters by fruit juices to decrease drug bioavailability. This newly proposed mechanism of action and its effect vis a vis various medications also demands further investigation [25,29].

Assessment of the in vitro CYP inhibition potential for these natural products has important implications for predicting the likelihood of natural product-drug interactions if these products are taken concomitantly. The susceptibility of CYP3A4 to modulation by food constituents may be related to its high level of expression in the intestine, as well as its broad substrate specificity. Reported ethnic differences in the activity of this enzyme may be partly due to dietary factors. Food-drug interactions involving CYP1A2, CYP2E1, glucuronosyltransferases and glutathione S-transferases have also been documented, although most of these interactions are modest in magnitude and clinically relevant only for drugs that have a narrow therapeutic range. Recently, interactions involving drug transporters, including P-glycoprotein and the organic anion transporting polypeptide, have also been identified. Hence a lot of food varieties have the potential to require dosage adjustment to maintain drug concentrations within their therapeutic windows, especially with drugs that have a high first pass degradation [30]. Further research is needed to determine the scope, magnitude and clinical importance of food effects on drug metabolism and transport.

Relevant phytochemistry

Another area in which the search for definite answers continues, is the quest to find the active constituents of grapefruit juice that are responsible for its actions on CYP enzyme systems and Pgp. The components of grapefruit juice that are responsible for clinical drug interactions have yet to be fully determined but the compounds thought to be responsible for this action include flavonoid glycosides (narirutin, naringin, naringinen, quercetin, kaemferol, hesperidin, neohesperidin, didymin, and poncirin) [8,31-34], furanocoumarins (6',7'-dihydroxybergamottin, bergamottin) and sesquiterpen (nootkatone)[8,22,32,35,36].

Flavanoids exist in grapefruit juice in the form of glycosides, with naringin being the most abundant. Upon ingestion, these are converted to aglycones and sugars by the action of intestinal flora. Being polyphenolic and electron rich, these compounds can theoretically inhibit the CYP enzymes. However, studies have at most shown an in vitro effect by these compounds on the these enzymes and have failed to identify any in vivo effect by them [37,38], leading to an implication that they are probably not the main active ingredients of grapefruit juice [1,39]. Studies have even failed to demonstrate any sort of activity in naringin although its metabolite naringinin was observed to be active in vitro. Yet, because of their huge quantities in grapefruit juice, and the fact that naringin is not present in other citrus juices, flavanoids remain a subject of research.

The main focus at present, however, is on furanocoumarins. This group includes Bergamottin, its derivative 6' 7' dihydroxybergamottin (DHB) and a host of other compounds [40]. Controversy still exists on the degree of their role in the inhibitory effects of grapefruit juice. Several studies have shown DHB [23,35,40] and to an extent Bergamottin [23] to be important contributors to the grapefruit juice effect. In one study, the inhibitory potency of DHB and four recently isolated furanocoumarins, when mixed with one another, almost approached that of grapefruit juice. Omission of any of the components resulted in decreased potency, suggesting that all major furanocoumarins contribute to the inhibitory effects of grapefruit juice [40]. However, others have suggested that DHB and Bergamottin are not the primary substances responsible for inhibition of CYP activity clinically [41,42]. For now, this topic also remains a subject of intense research.

Drug-grapefruit juice interactions
Anti-hypertensive drugs and amiodarone

1,4-Dihydropyridine calcium antagonists are lipid soluble drugs used in the treatment of essential hypertension and angina pectoris and metabolized in vivo by CYP3A4. Since the effects of grapefruit juice were first noticed with felodipine, this class of drugs has been intensively studied with grapefruit juice. The degree to which the intestinal CYP system metabolizes this class of drugs and affects their oral bioavailability varies markedly. In a study done by Lundahl J et al., it was found that the intake of grapefruit juice led to an increase in the oral bioavailability by 112% [43]. However, this study also found out that the intravenous pharmacokinetics of felodipine were not significantly altered with grapefruit juice. The main acute effect of the grapefruit juice on the plasma concentrations of felodipine was believed to be mediated by inhibition of gut wall metabolism. Grapefruit juice-felodipine interaction increases with increasing frequency and amount of grapefruit juice ingestion, hence it has been determined that an interval of 2–3 days between grapefruit juice intake and felodipine administration is necessary if the interaction is to be avoided [44]. Blood pressure responses to felodipine with grapefruit juice have also been assessed in the elderly and the systolic and diastolic blood pressures were found to be lower with grapefruit juice in the single-dose state, whereas they were not different between treatments in the steady-state dose [45]. The different blood pressure results between the studies can be explained by felodipine concentration-blood pressure response relationships. The elderly should be particularly cautioned about concomitant grapefruit juice and felodipine ingestion.

In the benzothiazepine calcium channel antagonists group, diltiazem has been found to have an increased bioavailability on co administration of a single intake of grapefruit juice. Inhibition of intestinal metabolism and/or P-glycoprotein efflux transport was believed to be possibly responsible for this effect [46]. However in contrast to this, another study showed the bioavailability to be unchanged with grapefruit juice suggesting that factors other than biotransformation may be contributing [47].

Compared with water, grapefruit juice increased the maximum concentration of nisoldipine and reduced the time to reach maximum nisoldipine concentration [48]. However, the effects of grapefruit pulp intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics [49].

A clinical study was performed to see the duration of this interaction in the body. Eight healthy volunteers were given grapefruit juice at 14, 38, 72 and 96 hours. Compared with the control group, the maximum plasma concentration of nisoldipine was significantly increased after grapefruit juice intake in at 0 and 14 hours, and the plasma concentration was significantly increased at each time till 72 hours [50]. It is therefore necessary to withhold grapefruit juice for at least 3 days before administration of the drug to prevent grapefruit juice -nisoldipine interaction.

Regarding verapamil, there are conflicting reports about its interaction with grapefruit juice. One study showed an increase in its bioavailability at steady state [51] while another showed no significant change in pharmacokinetics on a single administration.

ACE-inhibitors like enalapril, captopril, lisinopril and ramipril have not shown any interaction with grapefruit juice although such an interaction might be possible with angiotensin II type 1 receptor antagonists like losartan and valsartan [18]. Thiazide diuretics and alph 1 adrenergic antagonists (doxazosin, terazosin, prazosin) have also shown no interaction with grapefruit juice [18].

Amiodarone, an antiarrythmic, is metabolized by CYP3A to N-desethylamiodarone (N-DEA), a metabolite more potent than the parent drug [17]. On interaction with grapefruit juice, there has been shown to be complete inhibition of N-DEA production [52] leading to an overall decrease in the arrythmogenic side effects of amiodarone [17]. These results are in agreement with in vitro data pointing to the involvement of CYP3A in the metabolism of amiodarone and other Ca antagonists, suggesting that this interaction should be taken into account when prescribing this antiarrhythmic drug. Similarly grapefruit juice has been found to increase oral nimodipine bioavailability [53]. The same cannot be said of amlodipine, on which grapefruit juice has no appreciable effect [54].

One of the possible active ingredients in commercial grapefruit juice is Bergamottin, as mentioned before. This was determined after studying the effects of the furanocoumarin derivative on nifedipine (NFP) pharmacokinetics, suggesting that bergamottin in grapefruit might be the substance that elevates the NFP plasma concentrations [55].

Further studies have also been done to determine if even unprocessed grapefruit could cause drug interactions. It has been shown that unprocessed grapefruit can cause a drug interaction with felodipine [56]. 6', 7'-Dihydroxybergamottin and naringin were implicated to be more important in this case because they are present in higher concentrations in grapefruit extracts.


With antivirals, authors concluded that concomitant administration of grapefruit juice increases gastric pH and delays indinavir absorption but does not uniformly affect the systemic bioavailability of indinavir in HIV-infected subjects [57,58]. Similarly grapefruit juice has been shown clinically to not significantly affect amprenavir pharmacokinetics [59]. It is suggested that this may be because the primary metabolism of these drugs is not in the small intestine.

On the other hand regarding saquinavir, it has been shown that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute [60]. And since the antiretroviral effect of saquinavir is dose-dependent, it has been suggested that inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.

Amongst anti malarials, grapefruit juice significantly increases the oral bioavailability of artemether but does not prevent the time-dependent reduction in bioavailability or elimination half-life, suggesting a role for intestinal CYP3A4 in the presystemic metabolism of artemether [61,62]. Similar results have also been seen after a single oral dose of praziquantel with 250 ml of grapefruit juice [63].

Quinine appears to be unaffected in its pharmacokinetics. Since quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on quinine pharmacokinetics again supports the view that the site of CYP inhibition by grapefruit juice is mainly in the gut [17,64]. However for quinidine, grapefruit juice reduces its total clearance and increases the elimination half-life by 19% [65].

In antibiotics, administration of grapefruit juice increased the time to peak concentration of clarithromycin but did not affect other pharmacokinetic parameters [66] while in antiparasitics, albendazole showed an increase in bioavailability upon administration of grapefruit juice [67].

Benzodiazepines and CNS drugs

A marked interaction between oral midazolam and grapefruit juice has been found and the data is consistent again with a reduced first-pass metabolism of midazolam, resulting in increased bioavailability of midazolam [68,69]. The clinical importance of this is especially for patients with other causes for increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450. Thus, patients with liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4 substrates than subjects with normal liver function. Another important implication of this interaction is in dentistry. Oral midazolam is a frequently used sedative in pediatric dentistry. Although an oral form of midazolam is now commercially available, some practitioners continue to use the IV midazolam as an oral medication. If the injectible form of midazolam is administered orally, its bitter taste requires the use of a flavoring agent like grapefruit juice. This results in increased blood plasma levels of midazolam causing excessive levels of sedation for the pediatric patient. Grapefruit juice therefore should be contraindicated for use with oral midazolam especially in such patients [70]. Similar results have also been seen with triazolam [71].

One study however, did show that grapefruit juice did not have any particular interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in healthy young subjects [72]. However, since more studies have determined increases in midazolam and triazolam bioavailbility, grapefruit juice should be administered with caution with these drugs. However, alprazolam remains unaffected in pharmacokinetics or pharmacodynamics due to its high bioavailability [73].

Among antipsychotics, clozapine remained unaffected after consumption of regular-strength grapefruit juice, usually taken as 250 mL b.i.d., for 14 days [74]. One reason for this is that enzymes other than CYP3A4 also mediate clozapine disposition. Haloperidol remains unaffected by grapefruit juice [75].

In anti convulsants, grapefruit juice increases the bioavailability of carbamazepine [76] but does not affect the pharmacokinetics of phenytoin [77].

Grapefruit juice considerably increases plasma buspirone concentrations [78] and also increases sertraline bioavailability [79]. Grapefruit juice therefore should be contraindicated during administration of buspirone and sertraline.

Antihistamines and Serotonin Analogs

A number of studies have shown that a single glass of grapefruit juice produced an individual-dependent, variable increase in the systemic bioavailability of cisapride by inhibition of intestinal cytochrome P450 3A4 (CYP3A4) activity. [80-82] It has therefore been recommended that concomitant use of high amounts of grapefruit juice with cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia.

The effect of grapefruit juice on racemic nitrendipine was also to increase its bioavailability and it was found that it inhibits the stereoselective metabolism of nitrendipine in humans [83].

Regarding terfenidine, the ingestion of grapefruit juice leads to its enhanced systemic bioavailability [84,85]. This is especially important because the raised levels of terfenidine can prolong the QT interval in the electrocardiogram sufficiently to precipitate the ventricular arrhythmia of Torsade-des-pointes [86]. Incidentally, both terfenidine and cisapride have been globally withdrawn from the market due to serious cardiac arrythmias precipitated by their interaction with other drugs if simultaneously taken.

Statins and other cholesterol-lowering agents

Taking simvastatin first, the active ingredient bergamottin has been shown to inhibit simvastatin (SV) metabolism and increase the serum concentrations of simvastatin and its active metabolite simvastatin acid, and, to a lesser extent, those of active and total HMG-CoA reductase inhibitors [87,88]. The probable mechanism of this interaction was also the inhibition of CYP3A4-mediated first-pass metabolism of simvastatin by grapefruit juice in the small intestine. Bergamottin (BG) and naringenin (NRG) could therefore be applied as markers in food-drug interaction studies in order to adjust posology and the dose of simvastatin should be accordingly reduced.

Another study further found out that, when simvastatin is taken 24 hours after ingestion of "high-dose" grapefruit juice, the effect on the concentration of simvastatin is only about 10% of the effect observed during concomitant intake of grapefruit juice and simvastatin. It was also shown that the interaction potential of even high amounts of grapefruit juice with CYP3A4 substrates dissipates within 3 to 7 days after ingestion of the last dose of grapefruit juice [89].

The grapefruit juice effect has also been studied on lovastatin. Lovastatin and its active metabolite, lovastatin acid had greatly increased serum concentrations after grapefruit juice administration [90]. However, one other study has shown a minimal effect of a glass of regular-strength grapefruit juice on plasma concentration after a 40 mg evening dose of lovastatin [91].

Although grapefruit juice also increases the AUC of atorvastatin, the actual increase in activity is fairly modest, possibly due to a simultaneous effect of decreasing the AUC of active metabolites of atorvastatin [17]. Regardless, grapefruit juice should not be concomitantly ingested with atorvastatin, lovastatin or simvastatin. On the other hand, pravastatin, fluvastatin and rosuvastatin are three statin drugs that have been shown not to interact with grapefruit juice [18]. These may be useful alternatives in settings where there is a concern regarding potential interaction with grapefruit juice.

Other cholesterol-lowering agents like nicotinic acid and common fibric acid derivatives and bile acid sequestrants have shown no interaction, and therefore may be safely used, with grapefruit juice [18].


In patients with autoimmune diseases, the effect of chronic grapefruit juice administration on steady state blood concentrations of cyclosporine and metabolites is an increase in both parent and metabolite profiles [92]. This interaction was studied in renal transplant recipients. Administration of cyclosporine with grapefruit juice compared with water induced a moderate, butsignificant increase in the systemic exposure of cyclosporine [93,94]. Most of these studies involving cyclosporine were done on adult patients. However, one study was also done in the paediatric population. This study showed that alterations in cyclosporine absorption and elimination only occur with concurrent grapefruit juice ingestion when stable pediatric renal transplant patients are taking the oral cyclosporine solution, but not the microemulsion formulation [95].

Regarding prednisolone and etoposide, grapefruit juice has been found to have no significant effect on the metabolism of prednisolone [96] but in the case of etoposide, it has been shown to decrease its bioavailability [97].


In light of the wide ranging effects of grapefruit juice on the pharmacokinetics of various drugs, physicians need to be aware of these interactions and should make an attempt to warn and educate their patients regarding potential consequences of concomitant ingestion of these two items. Patient-to-patient variability should be kept in mind and elderly should be particularly warned about these interactions since they are more prone to grapefruit juice-drug interactions [17]. Physicians should also consider using these effects to their own advantage in order to reduce the dosage requirements of certain drugs. However, since further research is required into the mechanism of action of grapefruit juice, it is still premature to recommend it as an adjunctive booster with other drugs.


AUC = area under the plasma concentration-time curve

CYP = cytochrome P -450

DEA = desethylamiodarone

DHB = dihydroxybergamottin

HMG – CoA = 3 – hydroxyl – 3 – methylglutaryl coenzyme A

NFP = nifedipine

OATP = organic anion-transporting polypeptides

Pgp = P – glycoprotein

RDA = Recommended daily allowance

SV = simvastatin

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

Both authors contributed equally.


This was an independent review done by the authors.

Article information

Nutr J. 2007; 6: 33.
Published online 2007 October 30. doi:  10.1186/1475-2891-6-33
PMCID: PMC2147024
1Medical College, Aga Khan University, Stadium Road, Karachi, Pakistan
I'm me, not a statistic. Praying to not be one for years yet.

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