Wednesday, December 5, 2012

Grapefruit-medication interactions increasing

The Health Report

Grapefruit-medication interactions increasing

Presented by Dr Norman Swan

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Canadian researchers suggest that the number of prescription drugs that can have serious adverse effects from interactions with grapefruit are increasing.


Norman Swan: A paper just published in Canada has sounded a warning about an increased number of potentially life threatening interactions between grapefruit and some other fruits and a wide range of medications.

David Bailey is one of the authors. He's a Clinical Pharmacologist at the Lawson Health Research Institute in London, Ontario. He was the first to describe this phenomenon in a single drug a couple of decades ago.

David Bailey: That's correct, yes, it was more than 20 years ago.

Norman Swan: And how did you discover it in the first place?

David Bailey: Well, I've always been interested in drug interactions, and originally we started out with the idea of investigating the interaction between alcohol and a blood pressure lowering drug by the name of Felodipine. We wanted to do this properly, so we wanted to blind the subject as to whether they were getting their medication with alcohol or not. What we needed was a vehicle in which to put it.

Norman Swan: Oh, so you disguised it with grapefruit juice.

David Bailey: Yes, after trying everything we could find in the refrigerator one Saturday night.

Norman Swan: [laughs] You were cross-eyed by the time you actually made the discovery.

David Bailey: Yes, as we got toward the end there they got harder and harder to detect. But it was really my wife who said, you know, there's a can of grapefruit juice in the refrigerator, why don't you try that? And I defy you to taste the alcohol in grapefruit juice. So that's what we decided to do. We did a study, and there was an interaction with the alcohol and we did see a lowering of pressures and people did feel a little bit tilty. But, relevant to this conversation, what surprised us was in both the treatment groups—because one treatment group got the drug with just grapefruit juice as our negative control, and the other one got the drug with the grapefruit juice and the alcohol—the results showed that the blood levels of the drug Felodipine were four times higher than we would have expected relative to the dose that we had given.

Norman Swan: And there was no difference between the grapefruit juice and the grapefruit juice plus alcohol, so you concluded there must be something in the grapefruit juice.

David Bailey: Ultimately we worked our way backward and came up with it as the last possibility. So we decided, well, let's do a pilot study, and I said, well, I'll do it on myself. So I was the first person to test it in myself, and one day I did it in the clinic, we measured my blood profile for six hours and the levels were what I would have expected with water. And when I did it with grapefruit juice, my levels were five times higher. So right there we figured we had something pretty exciting, that is really what led us off to our very first publication in the Lancet describing this interaction.

Norman Swan: And these drugs are called calcium channel antagonists and there's a lot of them on the market for cardiac arrhythmias as well as for blood pressure lowering. And that has been well known amongst general practitioners and others for many years, that you don't take these calcium channel antagonists and an epine with grapefruit juice. But this more recent study suggests the list has become very long indeed.

David Bailey: Yes, that's correct, and not only that but there is a steep increase. There's a book that's available for every healthcare professional in Canada, it's called The Compendium of Pharmaceuticals and Specialties. I edit a section on drug administration and grapefruit juice.

Norman Swan: You're the go-to guy for grapefruits.

David Bailey: Yes. So the Canadian Pharmacists Association sends me new product monographs on a regular basis, monographs of new drugs coming on the market, and I track them as to will they interact with grapefruit juice and what is the possible clinical outcome. And what really began to surprise me is the number of new drugs that were coming out on a regular basis with the potential to produce not only an interaction with grapefruit juice and boost their level but the clinical consequences of that was really the possibility of overdose that produced very serious side-effects. That's why we went from really in 2008 17 of the drugs we would consider to be very serious, to 44. That's a long list of new drugs. And when we're talking about serious side-effects, we're talking about the possibility of sudden deaths from cardiac arrests, acute kidney failure, respiratory failure, gastrointestinal bleeding, suppression of bone marrow function, and the list kind of goes on from there. These really are serious phenomena.

Norman Swan: We'll come to the list in a moment. Why does grapefruit juice do this and not, say, another citrus juice like orange?

David Bailey: Well, because grapefruit juice has specific ingredients that affect a specific drug metabolising enzyme in the gastrointestinal tract. There is an enzyme in the gastrointestinal tract that is an extraordinarily important evolutionary enzyme that protects us from toxins that we consume in our environment. So it's a first-line enzyme. Every human being has this in their gut, it's one of these highly conserved enzymes. And basically what it does, in the process of a drug trying to pass from the gastrointestinal tract into the circulation, it will encounter this enzyme in the enterocyte lining the gut. And this is where a high percentage of this drug can be inactivated before it is absorbed into the bloodstream.

Norman Swan: So it is treated as if it was an ancient toxin but in fact it's just one of the barriers and hurdles that a drug has got to get through to get into the bloodstream and do its work.

David Bailey: That's exactly right, and this enzyme can do it very efficiently. Sometimes there's no drug that actually can make it into the systemic circulation unchanged, and they don't end up on the market, we never see them. But there are drugs that end up on the market that actually have very low bioavailability, which really is the percent of the oral dose that makes it into the systemic circulation unchanged. Now, Felodipine, which was the original drug we studied, has an oral bioavailability, on the average, of about 15%, which means that 85% of this drug is inactivated before it gets into the systemic circulation.

Norman Swan: And so the drug company that makes it loads up the dose to allow for that 85% destruction on the way through.

David Bailey: That's exactly right. They give a dose of, say, 10 mg with the idea of really getting only 1.5 mg into the bloodstream, and that will be enough to produce the clinical effect that we want in terms of lowering pressure.

Norman Swan: And grapefruit knocks off this enzyme.

David Bailey: And grapefruit juice knocks off this enzyme. And when I say knocks it off, I mean irreversibly inactivates this enzyme.

Norman Swan: Irreversibly?

David Bailey: Irreversibly inactivates it.

Norman Swan: So how long does it take the body to recover from a dose of grapefruit?

David Bailey: From a practical point of view it means that a dose of drug taken at any time, even if a drug is given once a day, no matter when in that dosing interval the grapefruit juice is consumed you have the possibility for an interaction. So the half life of recovery is somewhere around 12 hours, 24, on the average, even with a small dose of juice. This has been done with a small dose of juice. In any rate, from a practical point of view it means that when we say don't take grapefruit juice with your medication, what we mean is don't take grapefruit juice any time while you're on this medication because you could take your grapefruit juice in the morning and your medication at night and you'll still have an interaction, not necessarily as large but it's still there.

Norman Swan: And some of these drugs are pretty common. There is an antibiotic called Erythromycin, there's most of the commonest statins that people are on, you're risking muscle breakdown with grapefruit juice, and there's a couple of common drugs used when you've had a stent put in called Clopidogrel and Ticagrelor, they're affected too, and in fact you're suggesting loss of effectiveness, which means that you could get a clot in your stent.

David Bailey: Exactly right, and in actual fact that study has been done. Basically you can show that if somebody takes their drug Clopidogrel with grapefruit juice the anti-platelet effects are greatly attenuated.

Norman Swan: And you're suggesting with some drugs you could actually knock off your bone marrow. I mean, there are people listening who never take grapefruit juice and equally there is also more grapefruit juice in alcohol mixers these days. Is there any sense or measure of the effect of grapefruit juice in a practical sense on the population and the extent to which it is causing problems?

David Bailey: One thing you have to remember about this is that we are all different in terms of the magnitude of the increase. For example, if I just used Felodipine as our drug probe, which we have done in many studies, because even though the levels can go very high, basically it's not really a clinical problem. I mean, you might get a headache and a bit flushed and everything but...

Norman Swan: It is not going to kill you.

David Bailey: No, I've done it on myself lots of times. But what we find in all studies that I've done is that the average increase with a single glass of grapefruit juice, 200 mls, is about three-fold. So it goes from a bioavailability on the average of 15% to 45%. But the range is enormous because there is always somebody in the group on whom it has no effect whatsoever. As well I've seen people on the other extreme have it go up 10-fold. So even though the mean on the average is three times, there is a huge variance, and these individuals at the far end are the ones who are probably at the greatest risk. In most cases people can take their medication with grapefruit juice and they don't get into trouble because the levels don't go up that much, but there are a certain percentage and I don't know who they are, how big this percentage is, these people at the far end of the curve are the ones at the greatest risk.

Norman Swan: So what you're telling me is you don't really know how many thousands, hundreds or tens of people in Canada or Australia are actually ending up with problems because they've inadvertently had a regular grapefruit juice at breakfast.

David Bailey: Yes, we don't know the actual numbers. I think the bottom line in our paper was that we have to create a greater awareness. As one of my colleagues says, you know, we see somebody that comes into the emergency ward with acute renal failure, and our attention is drawn at basically solving that problem. People don't say, 'What changed in your diet in the last two weeks?' Adverse events are occurring but the question is...

Norman Swan: We're not pinning it on grapefruit.

David Bailey: Yes, that's exactly right. This article that we've written, it's an educational to sort of make people aware, especially with the fact that we have so many new drugs coming out in Canada that have a possibility of very serious side-effects, and we want people to be ahead of the loop in this and not have to worry about doing a body count later, but say let's be very careful with this. Because we cannot predict who these individuals are at the other end of the curve.

Norman Swan: And just to go on with the list without...we'll have a link to this on the Health Report's website, but it's a heap of new and very expensive anti-cancer drugs, there are antimalarial drugs, quite a few heart drugs, some affecting the central nervous system and so on. So it's a pretty comprehensive list which people should know about. So, grapefruit juice is off the menu for the time being if you're on a medication.

David Bailey: Yes, for those drugs, absolutely. When you're dealing with something as serious in terms of an adverse reaction with these drugs, the frequency may be small, which we don't know, but the consequences are dire, and it's an easy thing just to avoid grapefruit juice, it's a simple thing to do.

Norman Swan: So David, while I've got you here, given that you're the go-to guy for grapefruit, what other foodstuffs should you not be taking with your drugs?

David Bailey: Well, there are other fruits that are available that have been shown to do the same thing as grapefruit juice. There are Seville oranges, which are basically bitter oranges. We don't drink that...

Norman Swan: They make marmalade from them, don't they?

David Bailey: That's exactly right, we use them in marmalades. There are limes. We did a study with limes. And also pomelos. The commonality here is that they all contain the same active ingredients, which are furanocoumarins. The good news is that sweet oranges like naval and Valencia don't contain furanocoumarins and they don't cause an interaction.

Norman Swan: And what about other foodstuffs not related to this story, like milk? You are often told you either take this with food, take it after food, take it before food, it is thoroughly confusing. What's the story in general with food and taking medications?

David Bailey: Grapefruit juice and these others are kind of unique in the kingdom because usually food doesn't really make a great deal of difference. They kind of slow the appearance of the drug in the blood, you don't get as high a peak level, but the overall amount of drug that is absorbed is pretty close to the same in most circumstances. That's why when we came across this report of the grapefruit juice drug interaction, saying, well, these levels were five times higher, we had a credibility factor to overcome. Most people were very reluctant to believe our data. Of course now it is well accepted, but back in 1990 when we were trying to get this published in one medical journal, they just couldn't make up their mind. They sat on the fence because they didn't know what to do with it.

Norman Swan: So bottom-line, Seville oranges, pomelos and grapefruits steer clear of, other foods and taking your drugs with or without food might make a little bit of difference but certainly nothing like this.

David Bailey: Yes, exactly right. So it's very unique in this category. I might mention this other thing that is kind of important, it is relevant to this paper that we've got, and it's that nearly a quarter of the new drugs approved in Canada eventually get a serious safety warning or have to be pulled from the market for safety reasons. So this kind of underlines this whole idea of, yes, we know that a fair number of these new drugs that come out are already going to have, at least on a percentage basis, a serious warning come out after they've been marketed…

Norman Swan: So what you're suggesting is that some of these serious warnings might be inadvertent use of grapefruit.

David Bailey: Yes, could be. But that's why I say it is a real practical problem. So what we've got are these new drugs coming out, they've been out for three years or so, so they are still considered to be a new drug, but the circumstances under which the drug development occurs doesn't really give us a very good idea of what happens in the population general that gets the drug because all of the data that is used in drug development are with what we call randomised controlled trials, and the key word here is 'controlled'. So it's controlled in terms of who is allowed in the study, and it's controlled in terms of the circumstance of use of the drug. So you can be sure that they are going to exclude things like grapefruit juice and 3A4 inhibitors and a whole bunch of other things in their randomised clinical trials in order to get the best perspective in terms of efficacy relative to safety. But when we get out into the real world this isn't what happens. The population is far more varied, and the circumstance of use is far more different. And so it is not surprising that we start seeing these serious adverse events that are totally predictable once you get out into the real world. Why do we have to do a body count when we can say right from the start, look, we know there's going to be a problem here with grapefruit juice. It is not a matter of there's something wrong with the drug, it is not a matter of there's something bad about grapefruit juice, it's just the circumstance of use, so let's be prepared. If you want to use this drug, let's be cautious and let's make sure that grapefruit juice is not part of the equation.

Norman Swan: David Bailey is a Clinical Pharmacologist at the Lawson Health Research Institute in London, Ontario. And we'll have a link to that paper on our website. I've also been told that NPS, the National Prescribing Service, is updating its drug information on the grapefruit interaction and that'll be available online later on today or via their Medicines Line on 1300 MEDICINES, but I think that's just during working hours.

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